A direct synthesis of 1,7-dioxaspiro[4.5]decanes from the new 3-methylidenepentane-1,5-dianion synthon

Article abstract of DOI:10.1016/j.tet.2005.12.008

4-Phenylsulfanyl-2-(2-phenylsulfanylethyl)but-1-ene (2) has proved to be an appropriate and new 3-methylidenepentane-1,5-dianion synthon. The reaction of 2 with an excess of lithium powder and a catalytic amount of DTBB (2.5%) in the presence of a carbony

Full text of DOI:10.1016/j.tet.2005.12.008

Tetrahedron 62 (2006) 2264–2277
A direct synthesis of 1,7-dioxaspiro[4.5]decanes from the new
3
-methylidenepentane-1,5-dianion synthon
a
Francisco Alonso, Jaisiel Mel e´ ndez, Tatiana Soler and Miguel Yus
a
b
a,
*
a
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, and Instituto de S ´ı ntesis Org a´ nica (ISO), Universidad de Alicante, Apdo. 99,
E-03080 Alicante, Spain
b
Servicios T e´ cnicos de Investigaci o´ n, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 7 November 2005; revised 29 November 2005; accepted 2 December 2005
Available online 27 December 2005
Dedicated to Professor V ´ı ctor Riera on occasion of his 70th birthday
Abstract—4-Phenylsulfanyl-2-(2-phenylsulfanylethyl)but-1-ene (2) has proved to be an appropriate and new 3-methylidenepentane-1,5-
dianion synthon. The reaction of 2 with an excess of lithium powder and a catalytic amount of DTBB (2.5%) in the presence of a carbonyl
compound in THF at 0 8C, leads, after hydrolysis, to the expected methylidenic diols 3. These diols undergo double intramolecular
iodoetherification promoted by a silver salt, to furnish the corresponding 1,7-dioxaspiro[4.5]decanes (4) in very high yields. The oxidation of
compounds 4 to the corresponding lactones is also studied.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
X
Y
A variety of different methylidene dianion synthons have been
developed during the last decade in order to study their
reactivity and possible applications. Most of the attention has
been devoted to the trimethylenemethane dianion synthons (I)
since they are readily accessible and can react with one or two
electrophiles, allowing the incorporation of two equal or
I
X = or ≠ Y = Hal, TMS, Bun3Sn, OR, SR, SeR
X
1
Y
X
Y
differentmoieties,respectively. Theversatilityoftheresulting
II
III
structuresresidesonthepresenceofamethylidenicunit,which
can be subjected to further transformations. Less attention has
been paid, however, to trimethylenemethane dianion homo-
X = TMS; Y = SPh
X = or ≠ Y
2
Chart 1.
logue synthons such as 2-methylidenebutane-1,4- (II) or
3
-methylidenepentane-1,5-dianion (III) synthons (Chart 1).
On the other hand, spirocyclic ethers are widespread in
Nature and have attracted much attention from the synthetic
point of view. Especially abundant are the 1,5-
O
3
4
O
O
O
O
dioxaspiro[2.4]heptane and 1,7-dioxaspiro[4.4]nonane
O
O
skeletons, which can be found in many natural products
with interesting biological activities. Within the 1,n-
dioxaspiro[4.5]decane series, those in the ketal form like
O
n = 4
n = 6
n = 8
n = 7
Chart 2. 1,n-Dioxaspiro[4.5]decanes.
1
,4-dioxa- (Chart 2, nZ4) and 1,6-dioxaspiro[4.5]decanes
(
Chart 2, nZ6) are well known and easy to prepare, whereas
5
Keywords: Dianion synthon; Spirocyclic ethers; Intermolecular hydrogen
bonding; DTBB-catalysed lithiation.
compounds containing the 1,8-dioxaspiro[4.5]decane unit
Chart 2, nZ8) are less frequent but have also been deeply
studied in the last decade.
(
*
Corresponding author. Tel.: C34 965903548; fax: C34 965903549;
e-mail addresses: yus@ua.es; http://www.ua.es/dept.quimorg/
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.008

F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
2265
In contrast, the 1,7-dioxaspiro[4.5]decane moiety (Chart 2,
nZ7) is very uncommon in Nature and has been little
studied at a methodological and synthetic level. Thus, it can
be found, in its lactone form, in the structure of
camelliatannin G (IV, isolated from the leaves of Camellia
japonica and belonging to a family of complex tannins that
However, no report refers to the synthesis of 1,7-
dioxaspiro[4.5]decan-6-ones [see the spirocyclic unit high-
lighted in camelliatannin G (IV), Chart 3].
In recent years, we have shown an increasing interest in
developing new and versatile methylidenic dianion syn-
thons. As a result of different studies, we found out that
2-chloromethyl-3-chloroprop-1-ene (XI) and 2-chloro-
methyl-3-(2-methoxyethoxy)prop-1-ene (XII) allowed the
incorporation of two equal or different electrophilic
fragments, respectively, through a one-pot arene-catalysed
6
show anti-HIV activity) or in stemotinine (V) and
isostemotinine (isolated from the roots of Stemona tuberose
Lour., which are used in Chinese medicine as insecticides
and anticough agents). The mentioned unit is also present
7
in the widely studied reduction products of both artemisinin
and its derivatives (i.e., VI) as well as in a variety of
8
16
lithiation (Chart 4). These two dianion synthons were
successfully applied to the synthesis of fused bicyclic and
1
7
compounds with use as plant growth regulators and
herbicides (i.e., VII).
9
18
spirocyclic polyether structures. In a more recent study,
we have preliminary introduced 4-phenylsulfanyl-2-(2-
phenylsulfanylethyl)but-1-ene (2), as a new 3-methylidene-
pentane-1,5-dianion synthon that has found application in
the straight synthesis of 1,7-dioxaspiro[4.5]decanes and
Most of the synthetic chemistry directed to the preparation
of the title compounds involves specific carbohydrate
scaffolds in which different type of substituents on a
1
0
11
19
preformed tetrahydropyran or tetrahydrofuran ring are
subjected to intramolecular cyclisation. For instance, the
spirocyclic compound VIII was prepared by intramolecular
perhydropyrano[2,3-b]pyrans.
We want to report herein about the scope and limitations of
4-phenylsulfanyl-2-(2-phenylsulfanylethyl)but-1-ene (2) as
a dianion synthon by studying its reactivity against a large
variety of carbonyl compounds, including chiral ketones
and aldehydes. The resulting diols can be cyclised to the
corresponding 1,7-dioxaspiro[4.5]decanes under the pro-
motion of a silver salt. An improved method to oxidise 1,7-
dioxaspiro[4.5]decanes to the corresponding lactones is also
described.
1
1
six-membered lactol formation, whereas IX was obtained
by ring-closing metathesis of a 3-allyloxy-3-vinyl tetra-
1
2
hydropyran moiety. To the best of our knowledge there is
only one methodology that starts from a completely acyclic
precursor and gives the desired spirocyclic unit (but
unsaturated) in one step. This strategy gives rise to
spirocyclic dihydropyrans like X by double ring-closing
1
3
metathesis of a proper dioxatetraene precursor. A more
indirect route, also from an acyclic precursor, utilised the
ring-closing metathesis and hydroformylation reactions as
1
4
the key steps. 1,7-Dioxaspiro[4.5]decane lactones have
received even less attention and have been always
synthesized as 1,7-dioxaspiro[4.5]decan-2-ones [see the
2. Results and discussion
We tried first to prepare 4-phenylsulfanyl-2-(2-
phenylsulfanylethyl)but-1-ene (2) by nucleophilic
1
5
spirocyclic unit highlighted in stemotinine (V), Chart 3].
OH
HO
OH
OH
O
HO
HO
O
O
OH
O
O
O
HO
O
O
H
O
O
H
H
O
O
H
O
OH
H
HO
N
OH
O
HO
HO
O
H
H
O
O
O
OH
O
O
OH
VI
O
stemotinine (V)
HO C
2
OH
camelliatannin G (IV)
O
HO
O
H
O
OH
OBn
O
OMe
MeO
O
O
HO
O
O
Ph
O
O
O
H
O
VII
IX
X
VIII
Chart 3.

2266
F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
derived from cyclic ketones rendered structurally interesting
Cl
Cl
Cl
O
trispiro compounds in a very straight manner (Table 2,
entries 5–9). Among them, compound 4h (Table 2, entry 7)
is of a particular interest due to its trispirocyclic polyether
skeleton. Compound 4m (Table 2, entry 9) was obtained as a
OMe
XI
XII
Chart 4.
1
.73:1 mixture of diastereoisomers, the chiral nature of the
substitution from commercially available 2-chloromethyl-
-chloroprop-1-ene (1) and phenylthiomethyllithium,
precursor diol exhibiting, therefore, a low asymmetric
induction toward the generation of the new stereocentre in
the spirocyclic core. The presence of the 1,7-
dioxaspiro[4.5]decane moiety in compounds 4 was deter-
mined by spectroscopic means, and unequivocally estab-
lished by X-ray crystallography of compound 4j (Table 2,
entry 8) (see Section 3).
3
2
0
following Corey’s method. This reaction, however, failed
and instead, a variant had to be introduced involving the
organocuprate reagent derived from PhSCH Li and CuCN,
2
affording 2 in 82% yield (Scheme 1). Treatment of
compound 2 with an excess of lithium powder (1:7 molar
0
ratio) and a catalytic amount of DTBB (4,4 -di-tert-
butylbiphenyl, 1:0.1 molar ratio, 2.5 mol%), in the presence
It is noteworthy that, in contrast to the homologous 1,5-
dioxaspiro[2.4]heptanes,
or 1,7-dioxaspiro[4.4]nonanes,
2
1
1
8b
18a
of different carbonyl compounds (Barbier conditions) in
THF, at 0 8C for 2 h, led, after hydrolysis with water, to the
corresponding methylidenic diols 3 (Scheme 1 and Table 1).
A wide variety of ketones were studied as electrophiles
including linear (Table 1, entries 1 and 2), branched
1,6-dioxaspiro[3.4]octanes,
1
which exhibited in H
1
8c,d
NMR a standard AB system for the CH O group in the
2
tetrahydrofuran ring, in the present case the situation is quite
different. In fact, all the 1,7-dioxaspiro[4.5]decanes pre-
pared showed one of the CH O protons split (as a dd), inside
(
Table 1, entries 3 and 4), cycloalkyl substituted (Table 1,
entry 5), cyclic (Table 1, entries 6 and 7), heterocyclic
Table 1, entries 8 and 9) and polycyclic (Table 1, entry 10)
2
an AB system (see Section 5.4). This particular behaviour
was attributed to a long-range 4s-bond coupling involving
the equatorial protons attached to the carbon atoms 6 and 10
(
ketones, the corresponding methylidenic diols 3 being
obtained in modest yields after column chromatography.
More interesting was the use of the chiral ketones (K)-
menthone (Table 1, entry 11), (G)-norcamphor (Table 1,
entry 12), and (K)-fenchone (Table 1, entry 13) as
electrophiles. The reaction of the intermediate organo-
lithium species with these electrophiles led to the
4
Figs. 1 and 2). The different J
(
the 0–2 Hz range expected for that spin–spin coupling in
values observed lie in
eq–eq
2
cyclohexanes, what additionally confirms the presence of
2
a tetrahydro-2H-pyran ring.
We devised the possibility to transform diols 3 into
the corresponding 1,7-dioxaspiro[4.5]decan-6-ones by
oxidation adjacent to the tetrahydropyran oxygen atom.
Compound 4b was used as a model substrate and subjected
to the ruthenium-catalysed oxidation under the conditions
described in the literature and applied by us to other
homologue spirocyclic ethers.
ever, showed to be reluctant to oxidation when treated with
corresponding C -symmetric diols as single diastereo-
2
isomers. The nucleophilic attack to the carbonyl group
was equatorial for (K)-menthone and exo for (G)-
norcamphor and (K)-fenchone, diols 3k and 3m being
obtained as single enantiomers. A crystallographic study of
compounds 3l and 3m is included in Section 3. In contrast to
the reactivity exhibited by ketones, aldehydes were some-
what more reluctant to react under the above described
conditions. Nonetheless, an example using pivalaldehyde is
included, which gave a ca. 1:1 mixture of diastereoisomers.
2
3
1
8b–d
This compound, how-
a catalytic amount of RuO (0.15 equiv) and an excess of
2
NaIO (4.88 equiv), in CCl –H O (1/1) at rt (Scheme 3).
4
4
2
Thus, only 29% conversion was obtained after the standard
reaction time of 24 h (Table 3, entry 1). A moderate
conversion of 61% was reached after 1 week, whereas the
more desired 95% conversion was only achieved after a
prohibitive reaction time of 36 days (Fig. 3). We made an
effort in order to improve the above mentioned results by
varying the different parameters involved in this transforma-
tion, namely: the ruthenium catalyst, the stoichiometric
oxidising agent, the solvent, presence or absence of a phase-
transfer agent, as well as the reaction conditions. As it is
shown in Table 3, very poor results were obtained in most
cases, independently of the parameters and reaction
conditions used. Even the methodology developed by
Balavoine et al. for the oxidation of cyclic ethers, involving
With the methylidenic diols 3 in hand, we tried to cyclise
them under our previously published iodoetherification
1
8
conditions. However, the reaction with the system I2,
Ag O, dioxane/H O 7:1, rt, gave mainly the intermediate
iodohydrin, whereas the starting diol remained practically
2
2
unaltered with the system NaH, THF, I , 0 8C to rt. New
2
reaction conditions were developed and optimised by
varying the base (Na CO , Et N) and the silver source
2
3
3
(
AgOTf, and Na CO in THF at rt. Under those reaction
AgOTf, AgOAc), the best results being achieved using I2,
2
3
conditions, some of the diols 3 readily underwent double
intramolecular cyclisation to the corresponding 1,7-dioxa-
spiro[4.5]decanes 4 in excellent isolated yields without any
further purification (Scheme 2 and Table 2). It is worthy of
note that those diols containing electrophilic fragments
2
4
the use of hydrated RuCl , failed (Table 3, entry 10). We
3
observed, however, that, in general, these low conversions
were reached irrespective of the reaction time. From this
OH
R
OH
PhS
SPh
Cl
Cl
i
ii,iii
R
R
R
1
2
3
2 2 2
Scheme 1. Reagents and conditions: (i) PhSCH Li, CuCN, LiCl, 0 8C, 2 h; (ii) Li, DTBB (2.5 mol%), R CO, THF, 0 8C, 2 h; (iii) H O.

F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
2267
Table 1. Preparation of the methylidenic diols 3
a
Entry
Electrophile
Product 3
b
No.
Structure
Yield (%)
OH
OH
O
O
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
55
Et
Et
Et
Et
OH
OH
50
52
54
41
57
n-C H
n-C H
n-C H
5
11
5
11
4
4
n-C H
5
11
5
11
O
OH
OH
Pri
iPri
Pr
Pri
O
OH
OH
But
tBut
Bu
But
OH
OH
OH
OH
O
O
O
OH
OH
7
8
3g
3h
58
O
OH
OH
c
37
O
O
O
O
OH
OH
OH
OH
c
9
3i
3j
35
n
NPrn
Pr N
N
n
Pr
O
d
1
1
0
1
33
OH
HO
e
3k
3l
48
O
O
OH
OH
f
12
47
OH
HO
e
1
1
3
4
3m
3n
49
O
H
O
OH
OH
But
g
42
But
1
a
b
c
d
e
f
1
13
All products were R95% pure (GLC and/or 300 MHz H NMR) and were fully characterised by spectroscopic means (IR, H and C NMR, and MS).
Isolated yield after column chromatography, unless otherwise stated (silica gel, hexane/EtOAc), based on the starting compound 2.
Purification by column chromatography was carried out with EtOAc/MeOH as eluant.
Isolated yield after recrystallisation with hexane.
As a single enantiomer.
As a single diastereoisomer.
As a ca. 1:1 mixture of diastereoisomers.
g

2268
F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
R
R
3. X-ray crystallographic study
OH
R
OH
O
i
R
R
R
R
The structure of compounds 3l, 3m, and 4j was unequi-
vocally established by X-ray crystallography.
R
O
3
4
3
.1. Compound 3l [(G)-norcamphor derivative]
Scheme 2. I
2
, AgOTf, Na
2
3
CO , THF, rt, 5–12 h.
Figure 4 shows a single molecule of the diol 3l in which it
can be seen how the dianion attack to the carbonyl group of
Table 2. Preparation of the 1,7-dioxaspiro[4,5]decanes 4
a
Entry
Reaction time (h)
Product 4
b
No.
Structure
Yield (%)
Et
Et
O
Et
Et
1
2
3
12
12
12
4a
4b
4c
95
O
n-C H
5
11
O
O
O
O
n-C H
n-C H
5 11
5
11
96
94
94
95
n-C H
5
11
O
O
O
O
Pri
Pri
Pri
Pri
But
But
But
But
4
5
6
5
12
12
4d
4f
O
O
4g
99
94
O
O
7
8
12
6
4h
4j
O
O
O
98
O
O
c
90
9
6
4m
O
1
a
1
13
All products were R95% pure (GLC and/or 300 MHz H NMR) and were fully characterised by spectroscopic means (IR, H and C NMR, and MS).
Isolated yield of pure 4 from the reaction crude, unless otherwise stated, based on the starting diol 3.
Isolated yield after column chromatography (silica gel, hexane/EtOAc), based on the starting compound 3. Compound obtained as a 1.73:1 mixture of
diastereoisomers.
b
c
observation it might be inferred that the reaction proceeds
fast at the beginning but at some stage the catalyst gets
completely deactivated and interrupts the catalytic cycle.
This fact led us to try the addition of the catalyst and the
stoichiometric oxidising agent in several portions, this
method providing the best conversion within a reasonable
reaction time (Table 3, entry 13). By using this procedure,
R
HA
10
H
R
O
O
6
R
R
HB
several
representative
1,7-dioxaspiro[4.5]decanes
4Jeq–eq= 1.2–2.0 Hz
were transformed into the corresponding lactones, 1,7-
dioxaspiro[4.5]decan-6-ones, in fair yields (Chart 5).
Figure 1. Long-range 4s-bond diequatorial coupling in the tetrahydro-2H-
pyran ring of the 1,7-dioxaspiro[4.5]decanes 4.

F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
2269
(
G)-norcamphor took place following an exo direction,
giving rise to the corresponding endo diol. Interestingly,
intermolecular hydrogen bonding was observed involving
the four hydroxyl groups of two diol molecules (Fig. 5). A
cross-shape orientation of the two diol molecules minimised
steric hindrance facilitating the intermolecular hydrogen
bonding through a near-square arrangement of the four
hydroxyl groups. In addition, one of the diol molecules in
the asymmetric part of the unit cell exhibits a static disorder
for one of the norbornyl moieties, in such a way that 50% of
the molecules at that position have a symmetry binary axis,
whereas for the other 50% of the molecules this kind of axis
is absent (Fig. 5).
3.2. Compound 3m [(K)-fenchone derivative]
The structure of enantiomerically pure 3m could be also
confirmed by X-ray crystallographic analysis. In this case, as
in the case of compound 3l, an exo dianion attack to the
carbonyl group of (K)-fenchone was also preferred (Fig. 6). A
50% disorder is observed affecting the hydroxyl group
hydrogen (Fig. 6). At one of the positions, a hydrogen bond
is formed involving the hydroxyl group of a neighbour
molecule. At the other position, however, has no acceptor
within the bonding distance (Fig. 6). In the crystal, the
hydroxyl group hydrogen atoms are 50% located at the
positions showed in bold bond, whereas the other 50% are
located as shown in hashed bond (Figs. 7 and 8). In contrast
with the hydrogen bonding observed for diol 3l, in this case
each hydroxyl group is hydrogen-bonded to a different diol
molecule, thus leading to a wavy three-dimensional scaffold
1
Figure 2. Typical H NMR region for the CH
dioxaspiro[4.5]decanes 4.
2
O group of the 1,7-
n-C H
5
11
O
n-C H
n-C H
5
11
5
11
n-C H
5
11
O
O
4b
i
(Fig. 8).
n-C H
5
11
O
n-C H
n-C H
5
11
5
11
n-C H
5
11
3.3. Compound 4j
O
X-ray crystallographic analysis of compound 4j unequi-
vocally confirmed the presence of the 1,7-dioxaspiro[4.5]-
decane moiety in compounds 4 (Fig. 9). The crystal is a non-
merohedric twin, which can be solved after calculating the
5
b
2 4 4 2
Scheme 3. (i) RuO (cat.), NaIO , CCl , H O, rt.
2
5
twin law matrix using the ROTAX programme.
Table 3. Oxidation of compound 4b
Entry
Catalyst
Re-oxidant
Solvent
Additive
Physical activation
Time (h)
Conversion
a
(
%)
1
2
3
4
5
6
RuO
RuO
RuO
RuO
RuO
RuO
2
2
2
2
2
2
NaIO
NaIO
NaIO
NaIO
NaIO
NaIO
4
4
4
4
4
4
CCl
CCl
CCl
CCl
CCl
CCl
4
4
4
4
4
4
–H
–H
–H
–H
–H
–H
2
2
2
2
2
2
O
O
O
—
—
—
—
—
—
—
24
24
48
24
0.17
0.17C1
29
25
39
7
15
15
Thermal (50 8C)
Thermal (reflux)
—
MW (3–10 bar, 65–80 8C)
MW (3–10 bar, 65–80 8C)
followed by ultrasounds
—
O–MeCN
O–MeCN
O–MeCN
7
8
9
RuO
RuO
RuO
2
2
2
aq NaClO
aq NaClO
aq NaClO
aq NaClO
CCl
CCl
CCl
4
4
4
–H
2
–H
2
–H
2
O
O
O
—
TBAB
TBAB
24
24
0.17
24
24
24
5
13
14
12
31
30
48
61
b
—
MW (10 bar, 80 8C)
c
10
11
12
13
RuCl
RuCl
RuCl
RuCl
3
3
3
3
$xH
$xH
$xH
$xH
2
2
2
2
O
O
O
O
CH
CH
2
Cl
Cl
2
CTAB
NaIO
NaIO
NaIO
4
4
4
2
2
CTAB
CTAB
CTAB
Thermal or MW
—
Thermal (reflux)
CCl
CCl
4
–H
–H
2
O
O
d
4
2
a
b
c
d
Determined by GLC.
TBAB, tetra-n-butylammonium bromide.
CTAB, cetyltriethylammonium bromide.
Added together with NaIO as a water solution in five portions at intervals of 1 h.
4

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F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
100
90
80
70
60
50
40
30
20
10
0
0
10
20
30
40
t (d)
Figure 4. Plot showing the X-ray structure and atomic numbering for one
non-disordered molecule of the diol 3l.
Figure 3. Graphic showing the oxidation of compound 4b to 5b versus
time, under the conditions depicted in Scheme 3.
solvent and TMS as internal standard; chemical shifts are
given in d (ppm) and coupling constants (J) in Hz. Mass
spectra (EI) were obtained at 70 eV on a Shimadzu QP-5000
and Agilent 5973 spectrometers, fragment ions in m/z with
relative intensities (%) in parenthesis. HRMS analyses were
carried out on a Finnigan MAT95S spectrometer. Elemental
analyses were performed on a Carlo Erba CHNS-O EA1108
elemental analyser. The purity of volatile and the
chromatographic analyses (GLC) were determined with a
Hewlett Packard HP-5890 instrument equipped with a flame
ionisation detector and a 30 m capillary column (0.32 mm
diametre, 0.25 mm film thickness), using nitrogen (2 mL/
min) as carrier gas, TinjectorZ275 8C, TcolumnZ60 8C
n-C H
n-C H
5 11
5
11
O
n-C H
5
11
n-C H
5
11
O
O
5
b (61%)
Pri
Pri
Pri
Pri
O
O
O
5
c (51%)
(
3 min) and 60–270 8C (15 8C/min); retention times (tr)
O
are given under these conditions. Column chromatography
was performed using silica gel 60 of 40–60 microns. Thin-
layer chromatography was carried out on TLC plastic sheets
with silica gel 60 F254 (Merck). THF was directly used
without any purification (Acros, 99.9%). Lithium powder
was commercially available (MEDALCHEMY S.L.).
O
O
5
f (52%)
Chart 5. Oxidation of compounds 4b,c,f under the conditions shown in
Table 3, entry 13.
5.2. Procedure for the preparation of 4-phenylsulfanyl-
2-(2-phenylsulfanylethyl)but-1-ene (2)
4. Conclusion
In conclusion, we have developed a new 3-methylidene-
pentane-1,5-dianion synthon, which has demonstrated to be
very useful for the preparation of symmetrically substituted
methylidenic 1,7-diols. These diols can be transformed into
the corresponding 1,7-dioxaspiro[4.5]decanes in excellent
yields and in a straightforward manner under the promotion
of a silver salt. In addition, an improved method allows the
oxidation of the mentioned spirocyclic ethers to the
corresponding lactones.
n-BuLi (14.00 mL, 22 mmol) was added to a solution of
thioanisole (2.34 mL, 20 mmol) in dry THF (50 mL), the
resulting solution being stirred for 15 min at rt. Then, a
light-blue solution of LiCl (1.86 g, 44 mmol) and CuCN
(2.00 g, 22 mmol) in dry THF (50 mL) was added at 0 8C.
Once the deep-brown organocopper reagent was generated
(ca. 15 min), 2-chloromethyl-3-chloroprop-1-ene (1)
(1.17 mL, 10 mmol) was added at 0 8C. The mixture was
stirred for 2 h and hydrolised with water (10 mL), followed
by the addition of aq 25% ammonia (10 mL) and extraction
with hexane (3!30 mL). It is recommended to wash the
organic phase with more aq ammonia solution in the case of
some remaining emulsion. The organic phases were dried
5. Experimental
over anhydrous MgSO , the solvents were evaporated under
4
5
.1. General
reduced pressure (15 Torr), and the residue was purified by
column chromatography (silica gel, hexane/EtOAc), fur-
nishing 2.42 g (82% yield) of compound 2.
Melting points were obtained with a Reichert Thermovar
apparatus. Optical rotations were measured with a Perkin-
Elmer 341 polarimeter with a thermally jacketted10 cmcell at
approximately 20 8C. Concentrations (c) are given in g/
5.2.1. 4-Phenylsulfanyl-2-(2-phenylsulfanylethyl)but-1-
ene (2). Orange oil; t 19.00; R 0.35 (hexane); n (film)
K1
2
K1
100 mL and [a] values are given in units of 10 deg cm g
NMR spectra were recorded on a Bruker Avance 300 and
.
r
f
3073, 3057, 1644, 896, 737, 690 (C]CH), 1941, 1868,
(comb.); dH 2.36 (4H, t, JZ6.9 Hz, 2!
1
Bruker Avance 400 (300 and 400 MHz for H NMR, and 75
K1
1791 cm
CH CH S), 3.00 (4H, t, JZ6.9 Hz, 2!CH S), 4.88 (2H,
1
and 100 MHz for C NMR, respectively) using CDCl as
3
3
2
2
2

F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
2271
Figure 5. Two views of the hydrogen-bonding pattern between the hydroxyl groups of two molecules of the diol 3l in the asymmetric part of the unit cell. The
atoms are shown as spheres and the hydrogen atoms (except those involved in the hydrogen bonds) are omitted for clarity. Disorder components of the
norbornyl moiety are shown with a different type of bond.
s, H C]C), 7.20–7.40 (10H, m, 10!ArH); d 31.9 (2!
2
C
CH S), 35.4 (2!CH CH S), 112.0 (H C]C), 126.0, 128.9,
2
2
2
2
1
3
29.2 (10!ArCH), 136.3 (2!ArC), 145.7 (C]CH ); m/z
2
C
00 (M , 8%), 191 (34), 190 (46), 177 (10), 123 (100), 109
(
10), 77 (10). HRMS calcd for C H S 300.1006, found
18 20 2
3
00.0995.
5
.3. General procedure for the preparation of diols 3
A solution of 4-phenylsulfanyl-2-(2-phenylsulfanylethyl)-
but-1-ene (2) (300 mg, 1 mmol) and the corresponding
carbonyl compound (2 mmol) in THF (4 mL) was added to a
green suspension of lithium powder (50 mg, 7 mmol) and
DTBB (27 mg, 0.1 mmol) in THF (3 mL) at 0 8C. After
stirring for 2 h at 0 8C, the resulting mixture was hydrolysed
with water (5 mL), extracted with EtOAc (3!10 mL), and
the organic phases dried over anhydrous Na SO . The
Figure 6. Plot showing the X-ray structure and atomic numbering for diol
3m.
2
4
solvent was evaporated under reduced pressure (15 Torr)
and the reaction crude purified by column chromatography
[
silica gel, hexane/EtOAc (compounds 3a–g,k–n), EtOAc/
MeOH (compounds 3h,i)] or recrystallisation with hexane
compound 3j).
(
5.3.1. 3,9-Diethyl-6-methyleneundecane-3,9-diol (3a).
Colourless oil; t 14.08; R 0.38 (hexane/EtOAc 8:2); n
r
f
K1
(
film) 3384 (OH), 1644 cm
(C]CH); dH 0.87 (12H, t,
JZ7.5 Hz, 4!CH ), 1.48 (8H, q, JZ7.5 Hz, 4!CH CH ),
3
2
3
1
2
7
7
.52–1.65 (6H, m, 2!OH, 2!CH CH C]CH ), 2.00–
.10 (4H, m, 2!CH C]CH ), 4.75 (2H, s, H C]C); d
C
2 2 2
2
2
2
.8 (4!CH ), 30.0, 30.9, 36.4 (4!CH CH , 2!CH CH ),
3
2
3
2
2
4.6 (2!CO), 108.6 (H C]C), 150.7 (C]CH ); m/z 238
2
2
C
(
M K18, !1%), 209 (41), 191 (55), 149 (16), 141 (21),
1
1
38 (10), 137 (100), 136 (32), 135 (16), 125 (13), 124 (10),
23 (84), 121 (25), 109 (21), 107 (32), 96 (10), 95 (40), 93
(
(
11), 87 (78), 85 (13), 83 (23), 81 (36), 69 (25), 67 (14), 57
76), 55 (33). HRMS calcd for C H O 256.2402, (M K
C
1
6
32
2
Figure 7. Plot showing the 50% disorder (hashed bonds) observed for the
hydroxyl group hydrogen atoms in diol 3m.
C H ) 227.2006, found 227.2007.
2
5

2272
F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
Figure 8. Unit cell plot showing the intermolecular hydrogen bonding between molecules of diol 3m in the crystal. The hydrogen atoms, except the hydroxyl
group hydrogen atoms, have been omitted for clarity.
(
(
(
(
37), 151 (11), 149 (12), 141 (10), 137 (26), 135 (19), 123
25), 121 (21), 115 (26), 111 (57), 109 (48), 107 (14), 99
14), 97 (17), 95 (45), 93 (11), 83 (21), 81 (23), 71 (100), 69
51), 67 (13), 57 (13), 55 (28). HRMS calcd for C H O
0 40 2
2
3
12.3028, found 312.3028.
5.3.4. 3,9-Di(tert-butyl)-2,2,10,10-tetramethyl-6-methyl-
eneundecane-3,9-diol (3d). Colourless solid; t 18.43; Rf
r
0
.80 (hexane/EtOAc 8:2); mp 40–42 8C; n (KBr) 3367
K1
(OH), 1647 cm
(C]CH); dH 1.06 (36H, s, 12!CH3),
.70–1.85 (4H, m, 2!CH CO), 2.00–2.15, 2.35–2.45 (6H,
Figure 9. Plot showing the X-ray structure and atomic numbering for
compound 4j.
1
2
2
7
2
m, 2!OH, 2!CH C]CH ), 4.76 (2H, s, H C]C); d
C
2
2
2
8.6 (12!CH ), 31.8, 33.0 (2!CH CH ), 42.6 (4!CCH ),
3
5
(
8
0
.3.2. 9-Methylene-6,12-dipentylheptadecane-6,12-diol
3b). Colourless solid; t 23.75; R 0.45 (hexane/EtOAc
2
2
3
9.6 (2!CO), 108.6 (H C]C), 152.0 (C]CH ); m/z 350
2
2
r
f
C
K1
:2); mp 65 8C; n (KBr) 3426 (OH), 1022 cm (CO); dH
(
1
(
M K18, !1%), 238 (10), 237 (59), 209 (12), 167 (34),
55 (10), 143 (10), 137 (31), 109 (17), 87 (21), 85 (14), 83
40), 69 (10), 57 (100). Anal. Calcd for C H O : C, 78.20;
.89 (12H, t, JZ7.0 Hz, 4!CH ), 1.25–1.60 [38H, m, 4!
3
(
CH ) , 2!CH CH C]CH , 2!OH], 2.00–2.10 (4H, m,
!CH C]CH ), 4.74 (2H, s, H C]C); d 14.1 (4!CH ),
2 2 2 C 3
24 48 2
2
4
2
2
2
H, 13.12, found C, 78.25; H, 12.99.
2
2
7
2.6, 23.2, 30.0, 32.4, 37.4, 39.1 [4!(CH ) , 2!CH CH ],
2
4
2
2
5.3.5. 1,1,7,7-Tetracyclopropyl-4-methyleneheptane-1,7-
diol (3e). Colourless oil; t 17.26; R 0.42 (hexane/EtOAc
4.4 (2!CO), 108.6 (H C]C), 150.7 (C]CH ); m/z 388
2
2
C
(
M K36, 10%), 336 (26), 335 (100), 331 (11), 318 (18),
r
f
8
:2); n (film) 3483 (OH), 3084 (cyclopropyl CH), 1643
3
2
1
1
17 (69), 236 (11), 225 (27), 222 (11), 221 (59), 220 (29),
07 (19), 179 (20), 172 (11), 171 (90), 167 (15), 165 (33),
63 (19), 151 (16), 149 (16), 137 (13), 127 (11), 123 (14),
11 (18), 110 (19), 109 (22), 99 (49), 97 (29), 95 (34), 93
K1
(C]CH), 1020 cm
CH CH), 0.75–0.95 (4H, m, 4!CH), 1.70–1.80 (4H, m,
(CO); dH 0.30–0.50 (16H, m, 8!
2
2
!CH CH C]CH ), 2.20–2.35 (6H, m, 2!CH C]CH ,
2 2 2 2 2
2
!OH), 4.77 (2H, s, H C]C); d K0.6, 0.8 (8!CH CH),
2 C 2
(
(
14), 83 (33), 81 (30), 71 (43), 69 (41), 67 (15), 57 (23), 55
51). Anal. Calcd for C H O : C, 79.18; H, 13.29, found
C, 79.29; H, 13.81.
1
8.4 (4!CH), 30.4, 40.6 (2!CH CH CO), 70.8 (2!CO),
2 2
2
8
56
2
C
1
08.2 (H C]C), 151.0 (C]CH ); m/z 286 (M K18,
2 2
!
(
1%), 245 (11), 147 (11), 145 (13), 133 (16), 131 (21), 120
16), 119 (35), 117 (23), 111 (100), 108 (21), 107 (24), 106
5
.3.3. 3,9-Diisopropyl-2,10-dimethyl-6-methyleneunde-
cane-3,9-diol (3c). Colourless oil; tr 16.09; Rf 0.52
hexane/EtOAc 8:2); n (film) 3463 (OH), 1645 (C]CH),
(12), 105 (34), 95 (12), 93 (29), 92 (12), 91 (55), 81 (14), 79
(47), 77 (24), 69 (84), 67 (24), 55 (27). HRMS calcd for
C H O 304.2402, (M KH O) 286.2297, found
C
(
2
0
32
2
2
K1
1380, 1365, 1020 cm (CO); d 0.90–1.00 (24H, m, 8!
CH ), 1.60–1.70, 1.85–1.95 (10H, 2m, 4!CH, 2!
286.2301.
H
3
CH COH, 2!OH), 2.00–2.10 (4H, m, 2!CH C]CH ),
2
5.3.6. 1-{3-[2-(1-Hydroxycyclopentyl)ethyl]but-3-enyl}-
cyclopentan-1-ol (3f). Colourless oil; t 15.50; R 0.50
2
2
4
.74 (2H, s, H C]C); d 17.3, 17.6 (8!CH ), 30.7, 32.3
3
2
C
r
f
K1
(
(
(
2!CH CH ), 34.0 (4!CH), 77.2 (2!CO), 108.4
2
(hexane/EtOAc 8:2); n (film) 3384 (OH), 1643 cm
(C]CH); d 1.40–2.00 [22H, m, 2!(CH ) , 2!CH CH -
2
C
H C]C), 151.1 (C]CH ); m/z 312 (M , !1%), 251
46), 233 (33), 191 (10), 177 (22), 165 (20), 163 (20), 153
2
2
H
2 4
2
2
C]CH , 2!OH], 2.10–2.25 (4H, m, 2!CH C]CH ),
2 2 2

F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
2273
4
8
.76 (2H, s, H C]C); d 23.7, 31.3, 39.5, 39.7 (12!CH ),
2
dC 27.2, 27.5, 34.8, 36.8 (8!CH), 28.5, 33.0, 34.5, 35.2,
35.5, 36.9, 38.3 (14!CH ), 75.1 (2!CO), 108.8
C
2
2.4 (2!CO), 108.6 (H C]C), 150.9 (C]CH ); m/z 234
2
2
2
C
C
(
M K18, !1%), 150 (11), 147 (32), 139 (45), 135 (69),
(H C]C), 151.7 (C]CH ); m/z 384 (M , !1%), 349
2
2
1
1
34 (100), 133 (13), 122 (11), 121 (58), 120 (13), 119 (43),
09 (10), 108 (21), 107 (21), 106 (20), 105 (32), 95 (20), 94
(15), 348 (51), 337 (17), 218 (14), 217 (62), 216 (21), 214
(10), 213 (26), 206 (10), 205 (62), 201 (11), 200 (21), 187
(30), 161 (12), 152 (12), 151 (100), 149 (14), 148 (22), 135
(17), 121 (12), 107 (14), 105 (15), 95 (11), 93 (18), 91 (24),
81 (20), 79 (27), 67 (18), 55 (15). Anal. Calcd for C H O :
(
17), 93 (41), 92 (13), 91 (22), 85 (48), 83 (10), 82 (10), 81
48), 80 (22), 79 (41), 77 (11), 69 (15), 68 (12), 67 (51), 57
19), 55 (40), 53 (12). HRMS calcd for C H O 252.2089,
(
(
1
6
28
2
26 40 2
found 252.2097.
C, 81.20; H, 10.48, found C, 81.23; H, 10.48.
5.3.7. 1-{3-[2-(1-Hydroxycyclohexyl)ethyl]but-3-enyl}-
cyclohexan-1-ol (3g). Colourless oil; t 16.88; R 0.40
5.3.11. (1S,2S,5R)-1-(3-{2-[(1S,2S,5R)-1-Hydroxy-2-iso-
propyl-5-methylcyclohexyl]ethyl}but-3-enyl)-2-isopro-
r
f
K1
(
hexane/EtOAc 8:2); n (film) 3354 (OH), 1645 cm
C]CH); d 1.30–1.65 [24H, m, 2!(CH ) , 2!CH CH -
pyl-5-methylcyclohexan-1-ol (3k). Colourless oil; t 20.04;
r
(
C]CH ], 1.65 (2H, br s, 2!OH), 2.05–2.20 (4H, m, 2!
20
R 0.43 (hexane/EtOAc 8:2); [a] C4.7 (c 1.0, CHCl ); n
H
2 5
2
2
f
D
3
K1
film) 3457 cm (OH); d 0.75–1.00 (18H, m, 6!CH ),
2
(
H 3
CH C]CH ), 4.73 (2H, s, H C]C); d 22.2, 25.8, 29.3,
2
2
2
C
1
C]CH ), 1.95–2.10 (6H, m, 2!OH, 2!CH C]CH ),
.05–1.85 (22H, m, 6!CH, 6!CH CH, 2!CH CH -
2 2 2
3
1
1
1
1
1
7.3, 40.5 (14!CH ), 71.4 (2!CO), 108.6 (H C]C),
2 2
C
2
2
2
51.1 (C]CH ); m/z 280 (M , !1%), 244 (18), 201 (14),
2
4.76 (2H, s, H C]C); d 18.2, 22.5, 23.6, 25.6, 28.1, 47.9
2 C
65 (11), 164 (24), 161 (26), 153 (44), 150 (10), 149 (74),
48 (100), 147 (11), 136 (15), 135 (87), 134 (16), 133 (26),
22 (11), 121 (14), 119 (13), 109 (13), 108 (15), 107 (22),
06 (22), 105 (20), 99 (80), 96 (10), 95 (42), 93 (27), 91
(6!CH , 6!CH), 20.5, 30.5, 35.1, 39.4, 46.7 (10!CH ),
3 2
7
5.1 (2!CO), 108.7 (H C]C), 150.3 (C]CH ); m/z 392
2 2
C
(M , !1%), 209 (15), 204 (17), 191 (56), 189 (11), 177
(19), 175 (15), 163 (12), 162 (11), 161 (63), 155 (37), 151
(21), 150 (37), 149 (23), 147 (13), 138 (15), 137 (37), 135
(21), 123 (16), 121 (15), 119 (10), 111 (15), 109 (40), 108
(19), 107 (27), 105 (20), 97 (15), 95 (100), 93 (30), 91 (20),
(
(
15), 83 (10), 82 (10), 81 (82), 79 (30), 69 (20), 67 (32), 55
44). HRMS calcd for C H O 280.2402, found 280.2412.
1
8 32 2
5
.3.8. 4-{3-[2-(4-Hydroxytetrahydro-2H-4-pyranyl)-
83 (24), 82 (12), 81 (96), 79 (24), 71 (13), 69 (91), 67 (35),
ethyl]but-3-enyl}tetrahydro-2H-pyran-4-ol (3h). Colour-
less solid; t 17.59; R 0.51 (MeOH/EtOAc 1:9); mp 110 8C;
57 (21), 55 (66). HRMS calcd for C H O 392.3654,
found 392.3649.
2
6
48 2
r
f
K1
n (KBr) 3416 (OH), 1644 (C]CH), 1096 cm (CO); dH
.45–1.60 (12H, m, 2!CH CH C]CH , 2!CH CH -
OCH CH ), 2.10–2.30 (4H, m, 2!CH C]CH ), 3.70–
1
2
2
2
2
2
*
.3.12. (1R ,2S ,4S )-2-(3-{2-[(1R ,2S ,4S )-2-Hydroxy-
*
*
*
*
*
5
bicyclo[2.2.1]hept-2-yl]ethyl}but-3-enyl)bicyclo[2.2.1]-
2
2
2
2
3
dC 28.9, 37.6, 41.2 (2!CH CH C]CH , 2!CH CH -
.80 (10H, m, 2!OH, 4!CH O), 4.79 (2H, 2s, H C]C);
2 2
heptan-2-ol (3l). Colourless solid; t 18.17; R 0.41 (hexane/
r
f
2
2
2
2
2
EtOAc 8:2); mp 100–102 8C; n (KBr) 3383 (OH),
1644 cm (C]CH); d 1.05–1.15, 1.25–1.70, 1.85–2.00,
OCH CH ), 63.8 (4!CH O), 69.0 (2!CO), 109.5
2
2
2
K1
C
H C]C), 149.9 (C]CH ); m/z 266 (M K18, 2%), 167
2 2
11), 166 (10), 155 (22), 151 (14), 150 (26), 138 (24), 137
16), 122 (12), 121 (17), 120 (11), 119 (17), 110 (11), 109
42), 107 (24), 106 (10), 105 (17), 101 (51), 99 (38), 97 (22),
H
(
(
(
(
2
4
.05–2.25 (30H, 4m, 4!CH CH , 4!CH CH, 2!OH),
2 2 2
.76 (2H, s, H C]C); d 22.1, 28.5, 30.0, 38.7, 40.3, 45.8
2
C
(
4!CH CH , 4!CH CH), 37.1, 46.7 (4!CH), 79.6 (2!
2 2 2
C
CO), 108.7 (H C]C), 151.2 (C]CH ); m/z 304 (M , !
2
2
9
7
5
6 (100), 95 (14), 94 (10), 93 (23), 91 (17), 83 (50), 81 (19),
9 (24), 73 (15), 71 (42), 69 (12), 68 (15), 67 (21), 55 (55),
3 (21). Anal. Calcd for C H O : C, 67.57; H, 9.92, found
1%), 268 (24), 176 (45), 175 (21), 166 (12), 165 (100), 161
(
(
(
29), 160 (66), 148 (17), 147 (43), 133 (12), 132 (17), 131
15), 121 (11), 119 (20), 111 (47), 109 (12), 108 (19), 107
25), 106 (12), 105 (20), 95 (27), 94 (10), 93 (34), 92 (11),
1
6 28 4
C, 67.69; H, 10.01.
9
1 (29), 83 (34), 81 (33), 80 (16), 79 (36), 77 (13), 69 (11),
5.3.9. 4-{3-[2-(4-Hydroxy-1-propyl-4-piperidyl)ethyl]-
but-3-enyl}-1-propylpiperidin-4-ol (3i). Colourless oil; tr
68 (12), 67 (58), 66 (19), 55 (33). Anal. Calcd for C H O :
C, 78.90; H, 10.59, found C, 78.99; H, 10.5.
20 32 2
2
1
1
2
1.71; R 0.20 (MeOH); n (film) 3372 (OH), 1649 (C]CH),
f
K1
032 cm (CO); d 0.94 (6H, t, JZ7.49 Hz, 2!CH CH ),
H
3
2
.55–2.20 (20H, m, 2!CH CH C]CH , 6!CH CH N),
2
5.3.13. (1R,2S,4S)-2-(3-{2-[(1R,2S,4S)-2-Hydroxy-1,3,3-
trimethylbicyclo[2.2.1]hept-2-yl]ethyl}but-3-enyl)-1,3,3-
trimethylbicyclo[2.2.1]heptan-2-ol (3m). Colourless solid;
t 21.41; R 0.43 (hexane/EtOAc 8:2); mp 121–122 8C; [a]
r f D
K20.1 (c 1.1, CHCl ); n (KBr) 3507 (OH), 1642 (C]CH),
3
1072 cm
1.50, 1.60–1.75, 1.85–2.30 (24H, 3m, 2!CH, 4!CH CH ,
2!CCH CH, 2!OH), 4.76 (2H, s, H C]C); d 18.1, 22.6,
2
2
2
2
2
.50–2.70, 2.85–3.05 (14H, 2m, 2!OH, 6!CH N), 4.76
2
(
2H, s, H C]C); d 11.6 (2!CH ), 18.9 (2!CH CH ),
2 C 3 2 3
2
0
2
4
1
1
1
9.1, 35.3, 40.4 (2!CH CH C]CH , 4!COCH CH N),
2
2
2
2
2
9.1, 59.8 (6!CH N), 68.5 (2!CO), 109.7 (H C]C),
2
2
C
49.5 (C]CH ); m/z 366 (M , 3%), 224 (25), 198 (32),
K1
2
(CO); d 0.95–1.10 (18H, m, 6!CH ), 1.30–
H 3
80 (16), 170 (12), 154 (25), 150 (10), 145 (11), 142 (11),
41 (10), 140 (100), 137 (10), 124 (11), 98 (34), 86 (13), 72
2
2
2
C
(
16), 70 (16), 56 (14). HRMS calcd for C H N O
2
27.7 (6!CH ), 24.9, 30.7, 31.6, 34.0, 41.1 (4!CH CH ,
3 2 2
2
42
2
2
3
66.3246, found 366.3257.
2!CCH CH), 44.4, 52.8 (4!CCH ), 50.2 (2!CH), 81.1
2 3
C
2!CO), 108.3 (H C]C), 152.2 (C]CH ); m/z 388 (M ,
(
2 2
5.3.10. 2-{3-[2-(2-Hydroxy-2-adamantyl)ethyl]but-3-
enyl}adamantan-2-ol (3j). Colourless solid; Rf 0.61
!1%), 370 (26), 290 (10), 208 (10), 207 (60), 203 (12), 202
(16), 191 (10), 189 (20), 151 (12), 149 (21), 147 (20), 137
(11), 135 (14), 133 (18), 125 (41), 124 (12), 123 (74), 122
(13), 121 (18), 119 (10), 109 (22), 107 (37), 105 (15), 95
(19), 93 (17), 91 (10), 83 (14), 81 (100), 79 (16), 69 (48), 67
(
(
hexane/EtOAc 8:2); mp 167 8C (sub.); n (KBr) 3324
OH), 1650 cm (C]CH); d 1.50–2.25 (36H, m, 8!CH,
K1
H
1
4!CH ), 2.50 (2H, br s, 2!OH), 4.75 (2H, s, H C]C);
2 2

2274
F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
(
found C, 80.22; H, 11.29.
22), 55 (19). Anal. Calcd for C H O : C, 80.35; H, 11.41,
2
m, 8!CH ), 1.45–2.05 (10H, m, 2!CH CH , 2!CHCH ),
3 2 2 3
2.45–2.55 (2H, m, 2!CHCH ), 3.33, 3.44 (2H, AB system,
3
2
6
44
JABZ11.2 Hz); d 18.3, 18.5, 18.6, 18.7, 18.8, 18.9 (6!
C
5
.3.14. DL and meso-2,2,10,10-Tetramethyl-6-methyl-
eneundecane-3,9-diol (3n). Colourless solid; t 13.52; Rf
CH
3
), 23.6, 28.0, 31.9, 34.0 (2!CH
34.1 (4!CH), 67.9 (CH O), 77.2, 80.1, 90.4 (3!C); m/z
2 2
CH ), 27.6, 32.0, 33.4,
r
2
C
0
.50 (hexane/EtOAc 8:2); mp 65–67 8C; n (KBr) 3395
(CO); d 0.90 (36H, s,
295 (M K15, !1%), 268 (19), 267 (100), 249 (24), 231
(12), 179 (10), 163 (44), 137 (13), 129 (36), 125 (32), 121
(12), 112 (14), 109 (12), 107 (19), 97 (10), 95 (14), 93 (11),
83 (13), 81 (12), 71 (34), 69 (30), 59 (12), 55 (16). HRMS
calcd for C20
found 267.2319.
K1
(
OH), 1639 (C]CH), 1018 cm
H
1
4
3
2!CH ), 1.35–1.45, 1.60–1.80 (12H, 2m, 4!CH CH,
3
2
!OH), 2.00–2.15, 2.25–2.35 (8H, 2m, 4!CH C]CH ),
2
2
C
.15–3.25 (4H, m, 4!CH), 4.79 (4H, s, H C]C); d 25.7
2
H O 310.2872, (M KC H ) 267.2319,
38 2 3 7
C
(12!CH ), 29.4, 29.5, 33.4, 33.6 (4!CH CH ), 34.9 (4!
3 2 2
CCH ), 79.5, 79.6 (4!CH), 109.2, 109.3 (2!H C]C),
1
3
2
C
50.1, 150.2 (2!C]CH ); m/z 238 (M K18, 1%), 181
2
5
.4.4. 2,2,8,8-Tetra(tert-butyl)-1,7-dioxaspiro[4.5]decane
4d). Colourless oil; t 19.12; R 0.80 (hexane/EtOAc 9:1); n
(
(
18), 163 (45), 137 (30), 135 (13), 123 (22), 121 (18), 111
14), 109 (26), 107 (30), 100 (25), 97 (17), 96 (17), 95 (37),
(
r
f
K1
film) 1112 cm (CO); d 1.00–1.15 (36H, m, 12!CH ),
(
H 3
9
7
3 (32), 87 (14), 85 (44), 84 (10), 83 (100), 82 (21), 81 (32),
9 (14), 71 (16), 70 (20), 69 (46), 67 (16), 57 (73), 55 (29).
1
.20–2.00 (8H, m, 2!CH CH ), 3.35, 3.41 [2H, AB
2 2
4
system, JABZ11.7, 3.35 Hz (CH H O, Jeq–eqZ2.1 Hz),
eq ax
HRMS calcd for C H O 256.2402, found 256.2402.
16 32 2
3
.41 (CH H O)]; d 26.5, 27.7, 28.4, 28.6, 28.9, 29.2,
ax eq C
2
CH CH ), 42.9 (4!CCH ) 67.4 (CH O), 76.6, 79.5, 85.3
(
9.3, 29.5, 29.7, (12!CH ), 29.3, 30.8, 31.6, 32.9, (2!
3
5.4. General procedure for the preparation of 1,7-
dioxaspiro[4.5]decanes 4
2
2
3
2
C
3!CO); m/z 309 (M K57, 27%), 253 (11), 235 (23), 135
(
3
24), 109 (14), 57 (100). HRMS calcd for C H O
2
66.3498, found 366.3486.
4
46 2
Iodine (382 mg, 1.5 mmol) was added to a solution of the
diol 3 (1 mmol) in THF (10 mL) and the mixture was stirred
at rt for 5 min. After the addition of Na CO (159 mg,
2
3
0
0
00
1
.5 mmol) and AgOTf (771 mg, 3 mmol), a white-yellow
5.4.5. Trispiro[cyclopentane-1,2 -tetrahydrofuran-5 ,3 -
tetrahydro-2H-pyran-6 ,1 -cyclopentane] (4f). Colour-
less oil; t 14.17; R 0.61 (hexane/EtOAc 8:2); n (film)
0
0
000
precipitate was rapidly formed. Additional stirring for 24 h
was followed by filtration through a short column contain-
ing a layer of Celite over silica gel, using hexane as eluant.
Washing with a saturated solution of Na SO is
r
K1
f
1073 cm
3.33, 3.39 [2H, AB system, J Z11.5, 3.33 Hz (CH H O,
(CO); dH 1.30–2.15 (24H, m, 6!CH CH ),
2
2
2
3
AB
eq ax
4
recommended if the filtrate is coloured. The resulting
solution was dried over Na SO and the solvents evaporated
Jeq–eqZ1.9 Hz), 3.39 (CH H O)]; d 23.6, 23.9, 24.1,
ax eq C
2
4
33.5, 33.8, 33.9, 34.5, 36.4, 38.9, 39.3, 39.7 (6!CH CH ),
2
2
C
69.5 (CH O), 79.4, 83.2, 91.2 (3!C); m/z 250 (M , 3%),
under reduced pressure (15 Torr), giving a reaction crude
that contained the pure compound 4, which did not require
any further purification.
2
152 (55), 151 (13), 138 (27), 99 (100), 96 (11), 95 (29), 81
(10), 80 (16), 67 (12), 55 (10). HRMS calcd for C H O
26 2
1
6
2
50.1933, found 250.1940.
5.4.1. 2,2,8,8-Tetraethyl-1,7-dioxaspiro[4.5]decane (4a).
Colourless oil; t 13.04; R 0.67 (hexane/EtOAc 8:2); n (film)
r
f
0
tetrahydro-2H-pyran-6 ,1 -cyclohexane] (4g). Colour-
0
00
K1
5.4.6. Trispiro[cyclohexane-1,2 -tetrahydrofuran-5 ,3 -
1
2
052 cm
.05 (16H, m, 4!CH CH , 2!CH CH ), 3.27, 3.38 [2H,
(CO); d 0.75–0.95 (12H, m, 4!CH ), 1.25–
H 3
00 000
2
3
2
2
4
less oil; t
1
3
r
K1
15.94; R
f
0.60 (hexane/EtOAc 8:2); n (film)
AB system, JABZ11.3, 3.27 Hz (CH H O, Jeq–eq
Z
.0 Hz), 3.38 (CH H O)]; d 7.2, 7.7, 8.6, 8.7 (4!CH ),
ax eq C 3
eq ax
070 cm (CO); dH 1.20–2.10 (28H, m, 14!CH CH ),
.29, 3.40 [2H, AB system, JABZ11.4, 3.29 Hz (CH H O,
2
2
2
2
2
2
eq ax
9.3, 30.1, 30.9, 31.3, 31.6, 32.8, 33.3, 33.4 (4!CH CH ,
2
4
3
Jeq–eqZ1.9 Hz), 3.40 (CH H O)]; d 21.6, 22.0, 24.1,
ax eq
C
!CH CH ), 67.9 (CH O), 74.8, 79.8, 85.9 (3!C); m/z
2
2
2
C
54 (M , 1%), 225 (13), 189 (10), 154 (26), 153 (13), 140
24.2, 25.6, 26.2, 30.7, 32.8, 33.3, 37.7, 38.7, 39.5 (14!
CH CH ), 67.8 (CH O), 71.5, 79.5, 83.0 (3!C); m/z 278
2
C
2
2
(
(
13), 135 (21), 133 (11), 111 (19), 101 (100), 98 (12), 97
15), 57 (20), 55 (18). HRMS calcd for C H O 254.2246,
found 254.2229.
(
M , 7%), 166 (42), 165 (13), 152 (15), 113 (100), 109 (14),
5 (12), 94 (26), 81 (12), 67 (13), 55 (12). HRMS calcd for
C H O 278.2246, found 278.2222.
1
6 30 2
9
1
8 30 2
5
.4.2. 2,2,8,8-Tetra(n-pentyl)-1,7-dioxaspiro[4.5]decane
4b). Colourless oil; t 19.50; R 0.68 (hexane/EtOAc 8:2);
0
5.4.7. Trispiro[oxacyclohexane-4,2 -tetrahydrofuran-
(
n (film) 1067 cm (CO); d 0.85–0.90 (12H, m, 4!CH ),
1
r
f
K1
0
00
00 000
H
3
5 ,3 -tetrahydro-2H-pyran-6 ,4 -oxacyclohexane] (4h).
Colourless oil; t 16.99; R 0.50 (hexane/EtOAc 1:1); n
.20–2.15 (40H, m, 10!CH CH ), 3.24, 3.38 [2H, AB
2 2
4
r
K1
f
system, JABZ11.2, 3.24 Hz (CH H O, Jeq–eqZ1.2 Hz),
(film) 1102 cm
(CO); dH 1.40–2.15 (16H, m, 4!
eq ax
3
2
4
.38 (CH H O)]; d 14.1 (4!CH ), 22.6, 22.7, 23.1, 23.9,
4.1, 31.8, 32.4, 32.5, 33.0, 33.5, 34.3, 38.7, 39.4, 39.7,
0.2, (10!CH CH ), 67.9 (CH O), 74.6, 79.8, 85.4 (3!C);
CH CH O, 2!CCH CH C), 3.34, 3.41 [2H, AB system,
2 2 2 2
4
ax eq
C
3
JABZ11.6, 3.34 Hz (CH H O, Jeq–eqZ1.6 Hz), 3.41
eq ax
2
2
2
(CH H O)], 3.55–3.90 (8H, m, 4!CH CH O); d 32.0,
32.3, 33.0, 34.1, 35.4, 36.8, 38.9, 39.3 (4!CH CH O,
2 2
ax eq
2
2
C
C
m/z 422 (M , !1%), 351 (19), 186 (13), 185 (100). HRMS
calcd for C H O 422.4124, found 422.4103.
2!CCH CH C), 63.6, 63.7, 65.5, 65.6, 67.9 (5!CH O),
2 2 2
6
2
8
54
2
C
9.1, 77.2, 79.9 (3!CO); m/z 282 (M , 1%), 169 (13),
5
.4.3. 2,2,8,8-Tetraisopropyl-1,7-dioxaspiro[4.5]decane
4c). Colourless oil; t 15.33; R 0.66 (hexane/EtOAc 8:2);
168 (43), 167 (10), 154 (11), 115 (100), 109 (10), 96
(30). HRMS calcd for C H O 282.1831, found
282.1826.
(
n (film) 1382, 1365, 1065 cm (CO); d 0.80–0.95 (24H,
r
f
K1
16 26
4
H

F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
2275
0
0
00
5
.4.8. Trispiro[adamantane-2,2 -tetrahydrofuran-5 ,3 -
123 (15), 110 (50), 99 (10), 95 (12), 83 (10), 69 (16), 55 (20).
HRMS calcd for C H O 436.3916, found 436.3911.
00
000
tetrahydro-2H-pyran-6 ,2 -adamantane] (4j). Colour-
less solid; t 18.33; R 0.65 (hexane/EtOAc 8:2); mp 157–
2
8 52 3
r
f
K1
58 8C; n (KBr) 1011 cm (CO); d 1.50–2.25 (36H, m,
1
8
5.5.2. 2,2,8,8-Tetraisopropyl-1,7-dioxaspiro[4.5]decan-6-
one (5c). Colourless oil; t 16.35; R 0.38 (hexane/EtOAc
H
!CH, 2!CH CH , 10!CH CH), 3.27, 3.38 [2H, AB
2
2
2
r
f
K1
4
system, JABZ11.6, 3.27 Hz (CH H O, Jeq–eqZ1.7 Hz),
8:2); n (film) 1736 (C]O), 1112 cm (CO); d 0.80–1.00
H
eq ax
3
3
3
.38 (CH H O)]; d 27.1, 27.2, 27.5, 27.8, 29.3, 29.6,
8.3, 39.7 (8!CH), 30.4, 31.9, 32.8, 32.9, 33.4, 33.8, 33.9,
4.1, 34.2, 34.3, 35.8, 36.1, 37.9, 38.2 (10!CH CH, 2!
(24H, m, 8!CH ), 1.50–2.15 (12H, m, 4!CH, 2!CH CH );
3
d 17.3, 17.4, 17.9, 18.1, 18.5, 18.8, 19.0(8!CH ), 27.6, 29.5,
C 3
ax eq
C
2
2
2
32.6, 35.5 (4!CH ), 33.6, 33.9, 35.0, 36.1 (4!CH), 91.2,
2
C
92.2, 93.6 (3!C), 172.6 (CO); m/z 282 (M K42, 11%), 281
CH CH ), 67.4 (CH O), 75.4, 79.2, 86.1 (3!C); m/z 306
2
2
2
C
(
(
(
M K76, 2%), 284 (10), 151 (19), 135 (38), 134 (100), 119
16), 105 (15), 93 (29), 92 (44), 91 (27), 80 (10), 79 (24), 77
14). Anal. Calcd for C H O : C, 81.62; H, 10.01, found
(64), 278 (11), 263 (11), 253 (46), 235 (21), 217 (10), 168 (16),
155 (15), 153 (17), 149 (21), 125 (100), 111 (24), 107
(10), 69 (29), 55 (13). HRMS calcd for C H O 324.2664,
2
6
38
2
20 36 3
C
C, 81.63; H, 9.89.
(M KC H ) 281.2111, found 281.2122.
3 7
0
0
(5f).
00
5.4.9. Trispiro[{(1R,2S,4S)-1,3,3-trimethylbicyclo[2.2.1]-
heptane}-2,2 -tetrahydrofuran-5 ,3 -tetrahydro-2H-
5.5.3. Trispiro[cyclopentane-1,2 -tetrahydrofuran-5 ,3 -
0
0
00
00 000
(tetrahydropyran-2-one)-6 ,1 -cyclopentane]
0
0
000
pyran-6 ,2 -{(1R,2S,4S)-1,3,3-trimethylbicyclo[2.2.1]-
heptane}] (4m). Mixture of diastereoisomers (63:37).
Colourless oil; t 19.65 (major) and 19.72 (minor); R 0.65
Colourless oil; t 15.27; R 0.41 (hexane/EtOAc 8:2); n
r f
K1
(film) 1735 (C]O), 1090 cm (CO); d 1.30–2.10 (24H,
H
r
f
m, 12!CH ); d 22.1, 22.6, 23.8, 24.1, 25.9, 28.1, 30.0,
2
C
K1
and 0.68 (hexane/EtOAc 8:2); n (film) 1069 cm (CO); dH
32.2, 35.2, 35.7 (12!CH ), 79.9, 83.7, 86.4 (3!C), 172.9
2
C
(C]O); m/z 236 (M K28, 19%), 218 (16), 151 (26), 141
0
3
2
3
5
.80–2.10 (80H, m, 8!CH CH , 4!CH CH, 12!CH ),
2
2
2
3
.25–3.45 (4H, m, 2!CH O); d (major) 17.8, 19.4, 23.1,
2
(11), 139 (15), 138 (100), 109 (15), 96 (15), 95 (69), 94 (19),
81 (27), 80 (49), 79 (17), 67 (18), 55 (19). HRMS calcd for
C H O 264.1725, found 264.1721.
C
3.6, 28.0, 28.4 (6!CH ), 25.7, 25.8, 26.5, 29.4, 29.6, 29.9,
3
3.3, 34.9, 41.2, 41.3 (2!CH CH, 4!CH CH ), 44.6,
2
2
2
16 24 3
1.5, 53.1, 53.2 (4!CCH ), 49.3, 51.0 (2!CH), 70.4
3
(
CH O), 78.9, 81.5, 92.1 (3!C); dC (minor) 18.1, 21.9,
2
5.6. X-ray crystallography
2
3
4
2.2, 24.2, 27.7, 27.9 (6!CH ), 25.6, 25.9, 26.3, 28.6, 29.8,
3
0.3, 34.2, 34.9, 41.4, 43.2 (2!CH CH, 4!CH CH ),
2
All compounds studied were recrystallised from hexane.
Data collection was performed on a Bruker Smart
CCD diffractometer, based on three u-scan runs (starting
uZK348) at the values of fZ0, 120, 2408 with the detector
at 2qZK328. For each of these runs, 606 frames were
collected at 0.38 intervals. An additional run at fZ08 of 100
frames was collected to improve redundancy. The diffrac-
2
2
3.4, 46.2, 52.1, 53.3 (4!CCH ), 49.3, 49.4 (2!CH), 70.9
3
C
(
CH O), 78.2, 80.9, 92.1 (3!C); m/z (major) 386 (M ,
2
7
(
6
%), 305 (22), 304 (100), 222 (15), 219 (13), 218 (25), 206
48), 125 (11), 124 (10), 123 (18), 107 (13), 81 (43), 79 (10),
C
9 (18), 67 (10), 55 (10). m/z (minor) 386 (M , 9%), 305
(
(
(
22), 304 (100), 222 (14), 219 (15), 218 (28), 207 (10), 206
55), 125 (12), 124 (12), 123 (20), 109 (11), 107 (14), 81
49), 79 (11), 69 (20), 67 (11), 55 (12). HRMS calcd for
2
6
tion frames were integrated using the SAINT programme
and the integrated intensities were corrected for Lorentz-
polarisation effects with SADABS.
2
7
C H O 386.3185, found [386.3174 (major), 386.3186
2
6 42 2
(
minor)].
X-ray data for 3l. C H O , MZ304.46; monoclinic, aZ
2
0 32 2
˚
˚
˚
5.5. General procedure for the oxidation of 1,7-
dioxaspiro[4.5]decanes 4 to lactones 5
16.018(4) A, bZ11.695(3) A, cZ19.445(4) A, bZ
3
˚
94.389(6)8; VZ3632.1(1) A ; space group P 2(1)/c; ZZ8;
K3
K1
˚
D Z1.114 Mg m ; lZ0.71073 A; mZ0.069 mm
;
c
A solution of NaIO (1.04 g, 4.88 mmol) and RuCl $xH O
4
F(000)Z1344; TZ21G1 8C. The structure was solved by
3
2
28 2
(33 mg) in water (5 mL) was added in five portions at
intervals of 1 h over a solution of compound 4 (1 mmol) and
cetyltrimethylammonium bromide (CTAB) (10 mg,
direct methods and refined to all 5707 unique F by full
o
2
9
matrix least squares (SHELX97). All the hydrogen atoms
were placed at idealised positions and refined as rigid atoms.
0
was stirred for an additional hour, extracted with CCl (3!
.027 mmol) in CCl (5 mL) at reflux. The reaction mixture
Final wR2Z0.3760 for all data and 409 parameters; R Z
4
1
4
0.1218 for 2826 F O4s(F ).
o
o
5
mL), and dried over anhydrous MgSO . After evaporation
4
of the solvent at reduced pressure (15 Torr), the residue was
purified by column chromatography (silica gel, hexane/
EtOAc).
X-ray data for 3m. C H O , MZ388.61; orthorhombic, aZ
26 44 2
˚
˚
˚
12.4239(19) A, bZ15.247(2) A, cZ12.357(2) A; VZ
3
˚
2340.8(6) A ; space group C222(1); ZZ4; D Z
1
c
K3
K1
˚
.103 Mg m ; lZ0.71073 A; mZ0.067 mm ; F(000)Z
5.5.1. 2,2,8,8-Tetrapentyl-1,7-dioxaspiro[4.5]decan-6-
one (5b). Colourless oil; t 20.99; R 0.39 (hexane/EtOAc
864; TZ23G1 8C. The structure was solved by direct
2
methods and refined to all 1188 unique F by full matrix
8
2
r
f
K1
o
29
least squares (SHELX97). All the hydrogen atoms were
8
:2); n (film) 1735 (C]O), 1095 cm (CO); d 0.85–0.95
H
(
12H, m, 4!CH ), 1.20–2.15 (40H, m, 10!CH CH ); d
C
4.0, 14.1 (4!CH ), 22.5, 22.6, 23.1, 24.0, 24.3, 28.4, 32.1,
3
placed at idealised positions and refined as rigid atoms. Final
wR2Z0.1200 for all data and 140 parameters; R Z0.0421 for
3
2
2
1
3
8
3
1
2.2, 32.4, 35.4, 36.6, 38.2, 38.8, 38.9, 39.1 (20!CH ), 80.8,
2
1000 F O4s(F ).
o
o
C
6.9, 88.5 (3!C), 173.8 (C]O); m/z 407 (M K29, !1%),
90 (23), 365 (18), 338 (24), 337 (100), 321 (10), 237 (14), 225
X-ray data for 4j. C H O , MZ382.56; triclinic, aZ
26 38 2
˚
˚
˚
(
12), 224 (27), 168 (17), 167 (11), 166 (13), 155 (10), 153 (47),
6.4617(10) A, bZ11.1766(18) A, cZ14.176(2) A, aZ

2
276
F. Alonso et al. / Tetrahedron 62 (2006) 2264–2277
Farinosi, R.; Capranico, G. Cancer Res. 1997, 57,
1710–1716.
9
1
9.041(3)8,
˚
bZ96.642(3)8,
gZ90.790(3)8;
VZ
K3
3
ꢀ
003.7(3) A ; space group P1; ZZ2; D Z1.266 Mg m
;
c
K1
˚
lZ0.71073 A; mZ0.077 mm ; F(000)Z420; TZK
1
and refined to all 8481 unique F by full matrix least squares
4. For a review, see: Wong, H. N. C. Eur. J. Org. Chem. 1999,
1757–1765.
2
8
00G1 8C. The structure was solved by direct methods
2
o
5. See, for instance: (a) Eames, J.; de las Heras, M. A.; Jones,
R. V. H.; Warren, S. Tetrahedron Lett. 1996, 37, 4581–4584.
(b) Caggiano, L.; Fox, D. J.; House, D.; Jones, Z. A.; Kerr, F.;
Warren, S. W. J. Chem. Soc., Perkin Trans. 1 2002,
2634–2645.
2
9
(
SHELX97). All the hydrogen atoms were placed at
idealised positions and refined as rigid atoms. Final wR2Z
.1489 for all data and 254 parameters; R Z0.0606 for 4486
0
1
F O4s(F ).
o
o
6
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Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with
the Cambridge Crystallographic Data Center as supplemen-
tary publication numbers CCDC 288641-288643. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax:
C44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk or
http://www.ccdc.cam.ac.uk/data_request/cif).
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1
This work was generously supported by the Spanish
Ministerio de Educaci o´ n y Ciencia (MEC; grant
CTQ2004-01261) and the Generalitat Valenciana (GV;
grant no. GRUPOS03/135). J.M. also thanks the GV for a
predoctoral grant.
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