Regioselective synthesis of 1,7-dioxaspiro[4.4]nonanes from a trimethylenemethane dianion synthon

Article abstract of DOI:10.1016/j.tet.2004.10.101

2-Chloromethyl-3-(2-methoxyethoxy)prop-1-ene behaves as a versatile trimethylenemethane dianion synthon, precursor of a variety of methylidenic diols obtained by DTBB-catalysed lithiation in the presence of a carbonyl compound (E¹=R¹R²CO) in THF at -78 to 0°C, followed by the addition of an epoxide [E²=R³R ⁴C(O)CHR⁵] at 0 to 20°C and final hydrolysis. These diols undergo double intramolecular iodoetherification in the presence of iodine and silver(I) oxide in THF or dioxane-water, to give the corresponding 1,7-dioxaspiro[4.4]nonanes, which can be easily oxidised to a variety of 1,7-dioxaspiro[4.4]nonan-6-ones. These skeletons are present in a wide series of natural products.

Full text of DOI:10.1016/j.tet.2004.10.101

Tetrahedron 61 (2005) 3437–3450
Regioselective synthesis of 1,7-dioxaspiro[4.4]nonanes from a
trimethylenemethane dianion synthon
a
Francisco Alonso, Bruno Dacunha, Jaisiel Mel e´ ndez and Miguel Yus
b
a
a,*
a
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, Instituto de S ´ı ntesis Org a´ nica (ISO), Universidad de Alicante, Apdo. 99,
3080 Alicante, Spain
0
b
Servicio de Difracci o´ n de RaiosX da RIAIDT, Edificio CACTUS, Universidade de Santiago de Compostela, 15782 Santiago de Compostela,
A Coru n˜ a, Spain
Received 1 July 2004; revised 17 August 2004; accepted 15 October 2004
Available online 21 November 2004
Dedicated to the memory of Dr. Juan Carlos del Amo who died in the horrific terrorist attack of the 11th of March 2004 in Madrid.
Abstract—2-Chloromethyl-3-(2-methoxyethoxy)prop-1-ene behaves as a versatile trimethylenemethane dianion synthon, precursor of a
1
1 2
variety of methylidenic diols obtained by DTBB-catalysed lithiation in the presence of a carbonyl compound (E ZR R CO) in THF at K78
2
3
4
5
to 0 8C, followed by the addition of an epoxide [E ZR R C(O)CHR ] at 0 to 20 8C and final hydrolysis. These diols undergo double
intramolecular iodoetherification in the presence of iodine and silver(I) oxide in THF or dioxane–water, to give the corresponding 1,7-
dioxaspiro[4.4]nonanes, which can be easily oxidised to a variety of 1,7-dioxaspiro[4.4]nonan-6-ones. These skeletons are present in a wide
series of natural products.
q 2004 Elsevier Ltd. All rights reserved.
1
syringae). 1,7-Dioxaspiro[4.4]nonanes have also been
2
1. Introduction
used as valuable polycyclic scaffolds in the synthesis of
1
3,14
natural products (e.g., VIII, in zaragozic acid synthesis)
or have been obtained as a result of carbohydrate
1
,7-Dioxaspiro[4.4]nonanes and its derived lactones are
substructures present in a variety of natural products, some
of them with important biological activities. These types of
compounds are especially abundant within the family of the
labdane diterpenoids, some representatives of which are
prehispanolone (I) (a specific platelet activating factor
receptor antagonist, isolated from the Chinese herbal
1
5–18
modification (IX, X)
(Chart 1).
The unique structural nature of these spirocyclic compounds
has attracted the interest of many synthetic organic
1
9–21
chemists.
However, most of the research has focused
1
,2
medicine Leonurus heterophyllus),
3
leopersin J (II)
from Leonurus persicus), otostegins (from Otostegia
on the synthesis of spirocyclic g-mono- and bislactones, less
attention being dedicated to the 1,7-dioxaspiro[4.4]nonane
itself as a polycyclic ether. The methodologies described in
the literature normally involve the intramolecular cyclisa-
tion of a moiety attached to a preformed g-lactone or
tetrahydrofuran ring. As representative examples we can
mention: (a) the intramolecular Michael addition of a
(
fruticosa), or marrubiglobosin (from Marrubium
4
5
globosum). Some other naturally occurring compounds
containing the mentioned skeletons are sphydrofuran (III)
6
(a secondary metabolite produced by Actinomycetes),
cinatrin A (IV) (a potent inhibitor of rat platelet phospho-
1
9
3
-hydroxyalkyl group to
b) Reformatsky-type reaction on a tetrahydrofuran-3-one,
a
2-butenolide ring;
lipase A , from the fermentation broth of the microorganism
2
7
Circinotrichum falcatisporum), longianone (V) (from
(
followed by lactonisation; (c) lactonisation of 2-hydroxy-
2
2
8
,9
Xylaria longiana),
Hypericum chinense L.), or syringolides 1 and 2, and
secosyrins 1 and 2 (VII) (all from Pseudomonas
hyperolactone A (VI) (from
2
3,24
1
0
11
alkyl-g-lactone acids and related compounds;
radical cyclisation of a 4-(3-butynyloxy)-2,5-dihydro-2-
(d)
2
furanone; or (e) intramolecular ketalisation from a 2,2-
5
2
6
disubstituted tetrahydrofuran.
Keywords: 1,7-Dioxaspiro[4.4]nonanes; Arene-catalysed lithiation; Spiro-
lactones; Spirocyclisation.
*
On the other hand, in recent years we have shown an
2
Corresponding author. Tel.: C34 965903548; fax: C34 965903549;
e-mail: yus@ua.es
URL: http://www.ua.es/dept.quimorg/
7–31
increasing interest in the synthesis of bicyclic
spirocyclic
and
polyether skeletons as constituents of
3
2,33
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.101

3438
F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
Chart 1.
1
2
3
4
5
Scheme 1. (i) Reagents and conditions: (i), Li, DTBB (2.5 mol%), R R CO, THF, K78 to 0 8C, 3.5 h; (ii), R R C(O)CHR , 0 to 20 8C, overnight; (iii), H
iv), I , Ag O, THF or dioxane–H O (7:1), 20 8C, overnight.
2
O;
(
2
2
2
Table 1. Obtention of 1,7-dioxaspiro[4,4]nonanes from diols 2
a
a
Entry
Product 2
Product 3
b
c
No.
Structure
Yield (%)
No.
Structure
Yield (%)
1
2
3
4
5
2a
70
3a
98
2b
2c
2d
2e
43
55
68
57
3b
3c
3d
3e
96
d
97
e
88
99
96
6
2f
41
3f
f
7
8
2g
2h
33
54
3g
3h
70
92

F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
3439
Table 1 (continued)
a
a
Entry
Product 2
Product 3
b
c
No.
Structure
Yield (%)
41
No.
Structure
Yield (%)
g
–
9
1
2i
2j
3i
h
89
0
30
3j
11
12
13
14
2k
2l
50
51
59
40
3k
3l
91
89
90
92
2m
2n
3m
3n
i
15
2o
41
3o
90
j
1
1
6
7
2p
2q
43
40
3p
3q
93
k
92
a
b
c
d
e
f
1
All products were R95% pure (GLC and/or 300 MHz H NMR).
Isolated yield after column chromatography (silica gel, hexane/EtOAc or EtOAc/MeOH) based on the starting chloroether 1.
Yield of pure 3 from the reaction crude (unless stated otherwise) based on the starting diol 2.
Obtained as a 3.5:1 mixture of diastereoisomers (56% d.e.) ( C NMR).
13
1
13
Obtained as a 1:1 mixture of diastereoisomers ( H and C NMR).
Isolated yield after column chromatography (silica gel, hexane/EtOAc) based on the corresponding diol 2g.
Cyclisation of 2i proved to be difficult and led to the corresponding iodohydrin 4i in 97% yield, apparently, as a single diastereoisomer.
Obtained as a 12:1 mixture of diastereoisomers (85% d.e.) (GLC).
g
h
i
1
Obtained as a 3:1 mixture of diastereoisomers (50% d.e.) ( H NMR), the major diastereoisomer is shown.
1
Obtained as a 12:1 mixture of diastereoisomers (85% d.e.) ( H NMR), the major diastereoisomer is shown.
j
k
1
Obtained as a 13:1 mixture of diastereoisomers (86% d.e.) (GLC and H NMR), the major diastereoisomer is shown.
0
important biologically active compounds. In particular, and
in connection with the title topic, we reported the two-
step synthesis of 1,6-dioxaspiro[3.4]octanes from 3-chloro-
lithiation catalysed by DTBB (4,4 -di-tert-butylbiphenyl)
with concomitant one-pot incorporation of two different
electrophilic fragments, derived from a carbonyl compound
and an epoxide, respectively. The resulting methylidenic
diols (2) can be regioselectively cyclised in the presence of
iodine and silver(I) oxide, affording the expected 1,7-
dioxaspiro[4.4]nonanes (3) in high yields. In addition, these
compounds can be easily oxidised to the corresponding 1,7-
3
2
2
spiro[2.4]heptanes from 2,3-dichloroprop-1-ene. In both
-(chloromethyl)prop-1-ene
and
1,5-dioxa-
3
3
3
4–36
cases an arene-catalysed lithiation
3
under Barbier
and an iodine-mediated double intra-
7,38
conditions
molecular cyclisation were utilised as the key reaction
steps. We want to demonstrate herein that the above
mentioned methodology also allows a straight and ready
access to the synthesis of 1,7-dioxaspiro[4.4]nonanes using
2-chloromethyl-3-(2-methoxyethoxy)prop-1-ene (1) as
starting material. This compound undergoes a selective
3
9
dioxaspiro[4.4]nonan-6-ones 6. The present study covers
the scope and limitations of this methodology in the
synthesis of the title compounds including a wide range of
electrophiles and discusses in some detail the spirocyclisa-
tion reaction mechanism as well as the stereoselectivity

3440
F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
Chart 2.
observed. In addition, the structure of these compounds has
been confirmed by X-ray diffraction analysis carried out for
compound 3g.
electrophiles, including acyclic, cyclic, and heterocyclic
ketones, as well as two aldehydes, whereas monosubsti-
tuted, 1,1-disubstituted, spirocyclic, and bicyclic oxiranes
were used as the second electrophiles. In spite of the fact
that the yields of diols 2 are moderate, this methodology is
very advantageous since it allows the introduction of two
different electrophiles in a one-pot sequence. It is note-
worthy that even styrene oxide, which is prone to undergo
reductive ring opening under the reaction conditions, could
be introduced as a second electrophile in good yield (entry
2
. Results and discussion
The reaction of 2-chloromethyl-3-(2-methoxyethoxy)prop-
1
-ene (1) with an excess of lithium powder (1:7 molar ratio)
and a catalytic amount of DTBB (4,4 -di-tert-butyl-
0
biphenyl) (1:0.1 molar ratio, 2.5 mol%), in the presence of
4
, Table 1). In the case of using cyclohexene oxide as the
1
1 2
second electrophile, only the corresponding trans-dia-
stereomeric products were obtained (entries 15–17,
Table 1).
different carbonyl compounds (E ZR R CO; 1:0.95 molar
ratio) in THF, at temperatures ranging from K78 to 0 8C for
ca. 3.5 h, led to a reaction mixture, which was treated with
2
an excess of an epoxide as a second electrophile [E Z
3
4
5
R R C(O)CHR ; 1:3 molar ratio] at 0 to 20 8C overnight
giving, after hydrolysis with water, the corresponding
methylidenic diols 2a–q (Scheme 1 and Table 1). A wide
variety of carbonyl compounds were utilised as the first
This sequential incorporation of two electrophilic fragments
arises from the different reactivity of the carbon–chlorine
2
8–31
and carbon–oxygen bonds in arene-catalysed lithiations.
Thus, after the first chlorine–lithium exchange, a function-
4
0–42
alised organolithium intermediate XI isformed,
which by
1
reaction with a carbonyl compound (E ) gives the expected
alkoxide XII. This species can be lithiated at higher
temperatures to yield a new dilithiated compound XIII,
2
which by final reaction with an epoxide (E ) affords the
dialkoxide XIV, precursor of the diol formed 2 (Chart 2). The
mediocre yield observed for some of the diols 2 (Table 1) was
mainly due to competitive proton capture of carbanion XIII
from the reaction medium instead of reaction with the
corresponding epoxide.
Chart 3.
Scheme 2.
Scheme 3.

F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
3441
The isolated diols 2 were subjected to intramolecular
cyclisation by treatment with iodine (1.5 equiv) and silver(I)
oxide (1.5 equiv) in THF or a 7:1 mixture of dioxane–water
at room temperature overnight, affording the corresponding
disappointing 1:1 diastereomeric ratio, whereas a 3.5:1 ratio
was observed for diol 2c. Polyspirocyclic structures were
easily obtained by the incorporation of cyclic ketones and
spirocyclic epoxides in the starting diol (Table 1, entries
6–8). Symmetrically substituted dispirocyclic products 3g
and 3h were readily prepared by using a cyclic carbonyl
compound and its derived epoxide (Table 1, entries 7 and 8).
In particular, compound 3g was a solid and was subjected to
X-ray diffraction analysis in order to provide more evidence
about the presence of the 1,7-dioxaspiro[4.4]nonane
skeleton in all products 3 (see Section 3). Unfortunately,
cyclisation of diol 2i, derived from cyclohexanecarbox-
aldehyde and isobutylene oxide, stopped at the iodohydrin
stage, which however was apparently obtained as a single
1
,7-dioxaspiro[4.4]nonanes 3 in excellent yields and with
such a high purity that they did not need any further
purification (Scheme 1 and Table 1). Entries 1–5 in Table 1
show several monospirocyclic products. It is worth of note
that chiral racemic diols where obtained when 1-octene and
styrene oxides where used as second electrophiles (Table 1,
entries 3 and 4), and consequently some asymmetric
induction could be expected in the formation of the new
spirocyclic stereocentre. Spirocyclisation of diol 2d gave a
1
13
diastereoisomer (GLC, H and C NMR) (entry 9, Table 1).
On the other hand, diol 2j could be nicely cyclised to afford
product 3j as a 12:1 diastereomeric mixture. NOESY
experiments carried out on compound 3j did not provide any
information about the relative stereochemistry of the major
diasteroisomer. The heteroatom content in the whole
structure of compounds 3 could be increased by choosing
appropriate heteroatom-containing electrophiles. Thus,
Scheme 4. Reagents and conditions: (i) RuO
4.88 equiv), CCl –H O 1:1, 20 8C.
2 4
(0.15 equiv), NaIO
(
4
2
Table 2. Oxidation of 1,7-dioxaspiro[4,4]nonanes 3 to lactones 6
a
Entry
Starting compound
Product 6
b
No.
Structure
Yield (%)
1
2
3a
6a
98
3c
3e
6c
6e
95
98
3
4
3f
6f
97
91
5
6
3h
3o
3p
6h
6o
c
90
d
7
6p
93
a
1
All products were R95% pure (GLC and/or 300 MHz H NMR).
Yield of pure 6 from the reaction crude based on the starting compound 3.
b
c
d
13
Obtained as a 3.5:1 mixture of diastereoisomers (56% d.e.) ( C NMR), the major diastereoisomer is shown.
13
Obtained as a 12:1 mixture of diastereoisomers (85% d.e.) ( C NMR), the major diastereoisomer is shown.

3442
F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
dispirocyclic compounds 3k–m derived from tetrahydro-
H-pyran-4-one, N-propylpiperidin-4-one, and tetra-
3. X-ray diffraction studies of compound 3g
2
hydrothio-2H-pyran-4-one with isobutylene oxide, were
obtained in high yields (entries 11–13, Table 1). Even
more interesting is the trispiro compound 3n, derived from
N-propylpiperidin-4-one and 1-oxa-6-thiaspiro[2.5]octane,
which contains three different heteroatoms, oxygen, nitro-
gen and sulfur (entry 14, Table 1). The versatility of the
methodology was also demonstrated in the synthesis of
spirobicyclic ethers derived from an acyclic or cyclic ketone
and cyclohexene oxide. In this case, cyclisation of the chiral
racemic diols 2o–q exhibited some diastereoselectivity,
which was relatively high for compounds 3p and 3q [12:1
Different attempts to crystallise compound 3g led to very
small and irregular crystals which were not good enough to
be analysed by the single-crystal X-ray diffraction tech-
nique. On the other hand, the crystal structure determination
of organic compounds by means of X-ray powder diffrac-
tion has been developed in recent years. The data collected
by this technique, in contrast to the single-crystal technique,
have the inconvenience of peak overlapping. This limitation
increases for most of the organic molecules composed of
light atoms because of the decreasing of the peak intensity at
high scattering angles. We used conventional X-ray powder
diffractometers because, in contrast with the synchrotron
radiation, are easily available and not expensive.
4
5
(
85% d.e. and 13:1 (86% d.e.), respectively]. The structure
of the major diasteroisomers of 3o–q shown in Table 1 was
determined by NOESY experiments (see Section 5). This
result can be promising in the synthesis of chiral non-
racemic 1,7-dioxaspiro[4.4]nonanes by utilising enantio-
merically pure epoxides as second electrophiles.
We could not use conventional direct methods for the
structure solution because we were working with low
quality data. However, we could work with initial organic
structures as starting solutions and the support of other
1
13
It must be mentioned that spirocyclisation of the diol 2g
experimental techniques (IR, H and C NMR, MS and
HRMS). We located such starting solutions on an indexed
unit cell and refined it from the experimental diffraction
data. We report herein the best solution found, which is in
agreement with the structure proposed from other experi-
mental techniques presented.
(
entry 7, Table 1) could not be driven to completion, this
explaines the lower yield observed in the formation of 3g
70%) compared to the rest of compounds 3. However, this
(
reaction allowed the isolation of the corresponding
iodohydrin intermediate 4g (15%) (Chart 3). This fact,
together with the isolation of the iodohydrin 4i derived from
diol 2i gave us firm proofs about the mechanism of the
spirocyclisation reaction (Chart 3). From compounds 4g,i it
can be inferred that the first cyclisation involves the
nucleophilic attack of the epoxide derived hydroxylic
moiety onto the iodonium ion (XV) in a 5-exo mode,
followed by a nucleophilic displacement of iodide by the
ketone derived hydroxylic moiety (Scheme 2, route a).
The alternative cyclisation route involving 4-exo attack of
the ketone derived hydroxylic moiety and nucleophilic
displacement of iodide by the epoxide derived hydroxylic
moiety did not occur at all (Scheme 2, route b). Therefore,
the formation of 1,7-dioxaspiro[4.4]nonanes 3 is highly
regioselective to the detriment of the less favoured 1,6-
dioxaspiro[3.5]nonanes 5 (Scheme 2).
The samples were measured on a Siemens D5005
diffractometer with Bragg–Brentano geometry and with
46
twin G o¨ bel mirrors as optical setup. A Cu sealed tube
˚
[
l(Ka1)Z1.5406 A] was used operating at 40 kV and
3
0 mA. The pattern was collected in the 4!2q!45 range
with a step size of 0.028 and counting time of 40 s per step.
The sample was spun during the data acquisition in order to
get the best peak profile and minimise the preferred
orientation effect.
Once the data were collected with the greatest possible
quality, the pattern was indexed using the program suite
47
Crysfire. The accepted solution was suggested by the
48
49
programs DICVOL91 and LZONv6.23b, based on the
position of the 20 first peaks. The cell parameters, the zero
point, the background and the peak shape (pseudo-Voigt
function) were refined using the program Bruker AXS
With a mechanism of spirocyclisation in hand, we tried to
rationalize the diastereoselectivity observed in the cyclisa-
tion of compounds 2o–q by using 2p as a model compound.
Thus, the geometry and the heats of formation of the
diasteromeric intermediate iodohydrins were calculated and
50
Topas. The refined cell parameters were aZ6.4422(15),
bZ10.9992(26), cZ28.3696(7), and bZ99.627(28).
The systematic extinctions were consistent with the
suggested monoclinic space group P21/c. This solution
was also coherent with the expected values of density
for the supposed molecule (C H O ), since with
43
optimised with the semiempirical method PM3. As a
result, iodohydrin 4p was found to be 4.7 kcal/mol more
stable than the corresponding diastereoisomer epi-4p, which
is in fair agreement with the 85% d.e. observed for
compound 3p (Scheme 3).
2
5 36 2
Table 3
Cell
refinement
Structural
refinement
We believed that the spirocyclic compounds synthesized 3
could be used as adequate precursors of 1,7-dioxa-
spiro[4.4]nonan-6-ones 6, which are also present as
substructures in many natural products (see Chart 1). This
transformation was successfully accomplished with the
system composed of catalytic ruthenium(IV) oxide and
r_exp
r_exp_dash
r_wp
r_wp_dash
r_p
r_p_dash
weighted_Durbin_Watson
gof
3.00
2.94
3.75
3.46
27.44
26.92
15.63
15.45
0.61
37.81
34.90
22.51
21.87
0.53
4
4
sodium periodate, leading to the corresponding lactones 6
in remarkable yields and without any further purification
9.15
10.07
(
Scheme 4, Table 2).

F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
3443
3
˚
VZ1981.92(10) A we obtained ZZ4. In Table 3 it is
shown the agreement factors of the cell refinement.
5
1
CHEM 3D was used for the chemical modelling. We used
different configurations in agreement with the other
experimental analyses in order to test them with the
diffraction data. Firstly, we located the different molecular
solutions into the refined unit cell calculated with the F.O.X.
5
2
program from the experimental diffraction data. The best
positioning obtained corresponds to the parameters Chi2Z
4
1534.562, GoFZ26.78, RwPZ0.54, RpZ0.36. The
Rietveld method was used for the refinement of the
positions of non H atoms with isotropic thermal factors
using the Bruker AXS Topas program. Due to the low
quality of the experimental data (because of the high
overlapping and low intensity of the high angle peaks), we
Figure 1.
skeleton, a clear worsening of the obtained adjustments
being observed. Therefore, it is possible to conclude that the
technique of structural resolution by powder diffraction data
is sensitive to changes of the atomic positions or the nature
of atoms of the starting molecule, and that this technique has
allowed the confirmation of the structure of compound 3g
released the non hydrogen atomic positions within a box of
˚
0
.005 A for each cycle. Once the new values of the atomic
positions were calculated, the hydrogen positions were
constrained to idealised positions with the WinGx pro-
(Fig. 3) as it was suggested by means of spectroscopic
techniques.
53
gram at the end of each cycle. In the Figure 1 it is shown
the variation of the atomic positions of the first cycle
(
F.O.X. solution) with respect to the last one (in green).
The agreement factors of the last cycle of the refinement are
shown in Table 3, where 514 reflections were used. The
experimental pattern (in black), calculated (in red) and the
difference (in red) are shown in the Figure 2.
4. Conclusions
We have described herein a methodology that gives a
straight access to the synthesis of 1,7-dioxaspiro[4.4]-
nonanes and 1,7-dioxaspiro[4.4]nonan-6-ones from
2-chloromethyl-3-(2-methoxyethoxy)prop-1-ene. This
starting material behaves as a versatile trimethylenemethane
dianion synthon under arene-catalyzed lithiation conditions,
The resulting molecule was optimised by comparison with
other models in which the oxygen atoms were located at
different positions of the 1,7-dioxaspiro[4.4]nonane
Figure 2.

3444
F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
Figure 3.
allowing the one-pot incorporation of two different electro-
philic fragments derived from a carbonyl compound and an
epoxide. Iodine-promoted double intramolecular cyclisation
of the resulting diols provides the expected spirocyclic
ethers, which are easily oxidised to the corresponding
lactones, all in excellent yields as well as in a regio- and
stereoselective manner.
(164 mg, 1 mmol) and the corresponding carbonyl com-
pound (0.95 mmol) in THF (3 ml), was added over 1.5 h to a
green suspension of lithium powder (50 mg, 7 mmol) and
DTBB (27 mg, 0.1 mmol) in THF (3 ml) at K78 8C. The
mixture was allowed to reach 0 8C and then a solution of the
corresponding epoxide (3 mmol) in THF (3 ml) was added
over 1.5 h continuing the stirring for 8 h at room
temperature. The reaction mixture was hydrolysed with
water (5 ml), extracted with ethyl acetate (3!10 ml), and
the organic phase was dried over anhydrous sodium sulfate.
After removal of the solvent under reduced pressure
5. Experimental
(15 Torr), the resulting residue was purified by column
chromatography (silica gel, hexane/EtOAc; EtOAc/MeOH
5
.1. General
was used for compounds 2k–n,q) to yield compounds 2.
Compounds 2c,d,f,h,p were previously described by us.
The physical and spectroscopic data of new compounds
follow:
Melting points were obtained with a Reichert Thermovar
apparatus. NMR spectra were recorded on a Bruker AC-300
3
1
1 13
300 MHz for H NMR and 75 MHz for C NMR) using
(
CDCl as solvent and TMS as internal standard; chemical
3
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 instru-
ment equipped with a flame ionization detector and a 12 m
capillary column (0.2 mm diametre, 0.33 mm film thick-
5.2.1. 7-Ethyl-2-methyl-5-methylenenonane-2,7-diol
(2a). Colourless oil; t
n (film) 3388 (OH), 1639 (C]CH), 1133 cm (CO); d
0.87 (6H, t, JZ7.4 Hz, 4!CH CH ), 1.23 (6H, s, 2!
CH C), 1.47 (4H, q, JZ7.4 Hz, 2!CH CH ), 1.60–1.66
(2H, m, CH CH COH), 1.97 (2H, s, 2!OH), 2.20–2.25
(4H, m, 2!CH C]CH ), 4.79, 4.94 (2H, 2s, H C]C); d
8.0 (2!CH CH ), 29.2 (2!CH ), 30.8 (2!CCH ),
32.3 (CH CH COH), 42.0 (CH COH), 44.4 (CCH C),
);
11.04; R 0.33 (hexane/EtOAc 8:2);
r
f
K1
H
3
2
3
2
3
2
2
2
2
2
C
CH
3
2
2
3
3
CH
2
2
2
2
2
70.8, 74.7, (2!COH), 113.4 (H C]C), 147.1 (C]CH
2 2
C
ness), using nitrogen (2 ml/min) as carrier gas, Tinjector
Z
m/z 181 (M K33, 1%), 110 (13), 109 (16), 95 (74), 87 (85),
81 (14), 69 (21), 68 (27), 67 (14), 59 (25), 57 (88), 55 (19),
2
retention times (t ) are given under these conditions.
75 8C, TcolumnZ60 8C (3 min) and 60–270 8C (15 8C/min);
45 (98), 43 (100), 41 (41). HRMS calcd for C13H O
26 2
r
C
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
214.1933, (M KH O) 196.1827, found 196.1823.
2
5.2.2. 7-Ethyl-5-methylene-8-pentyltridecane-3,8-diol
(2b). Colourless oil; t 15.76; R 0.38 (hexane/EtOAc 8:2);
(
(
Merck). THF was directly used without any purification
Acros, 99.9%). Lithium powder was commercially
r
f
K1
n (film) 3361 (OH), 1640 (C]CH), 1030 cm (CO); dH
available (MEDALCHEMY S. L.). For the preparation of
-chloromethyl-3-(2-methoxyethoxy)propene, see Ref. 30.
0.75–0.95 (12H, m, 4!CH ), 1.25–1.60 (24H, m, 11!
3
2
CH CH , 2!OH), 2.05–2.20 (4H, m, 2!CH C]CH ),
2
2
2
2
Isobutylene, octene, styrene and cyclohexene oxides were
commercially available. The other starting epoxides
4.79, 4.94 (2H, 2s, H C]C); d 7.9, 8.1 (4!CH ), 29.3,
2 C 3
29.4, 29.7, 31.0, 31.6, 31.7, 44.5 (12!CH CH ,
2
2
(
a-methylstyrene, 2-pentylheptene, 2-methylideneadaman-
CH C]CH ), 74.4, 74.6 (2!COH), 113.4 (H C]C),
2 2 2
C
147.4 (C]CH ); m/z 290 (M K36, 5%), 261 (24), 233
tane, methylidenecyclohexane, 4-methylideneoxacyclo-
hexane, and 4-methylidenethiacyclohexane oxides) were
prepared from the corresponding ketones by reaction with
2
(15), 219 (48), 207 (43), 165 (15), 163 (16), 151 (18), 149
(20), 137 (22), 136 (11), 135 (54), 124 (21), 123 (52), 122
(13), 121 (26), 111 (11), 110 (20), 109 (45), 108 (11), 107
5
4
the ylide derived from trimethylsulfoxonium iodide.
.2. General procedure for the preparation of diols 2
A solution of 2-chloromethyl-3-(2-methoxyethoxy)propene
(
56), 105 (14), 99 (13), 97 (17), 95 (62), 94 (12), 93 (52), 91
(29), 87 (47), 83 (23), 81 (68), 79 (38), 77 (18), 71 (20), 69
53), 68 (12), 67 (51), 57 (48), 56 (11), 55 (100), 53 (15).
HRMS calcd for C H O 326.3185, found 326.3191.
5
(
2
1 42 2

F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
3445
K1
(EtOAc); n (film) 3396 (OH), 1639 (C]CH), 1097 cm
(CO); dH 1.23 (6H, m, 2!CH ), 1.45–1.80 (6H, m,
5
1
.2.3. 1,1-Dicyclopropyl-6-methyl-3-methyleneheptane-
,6-diol (2e). Colourless oil; t 12.82; R 0.23 (hexane/
r
f
3
EtOAc 8:2); n (film) 3355 (OH), 3051 (cyclopropyl C–H),
1
CH CH), 0.75–0.85 (2H, m, 2!CH), 1.24 (6H, s, 2!CH ),
CH CH COH, 2!CH CH O), 2.03 (2H, br s, 2!OH),
2
2.18–2.25 (4H, m, 2!CH C]CH ), 3.73–3.77 (4H, m, 2!
2 2
CH CH O), 4.82, 4.98 (2H, 2s, H C]C); d 29.3 (2!
2 2 2 C
2
2
2
K1
642 (C]C), 1030 cm (CO); d 0.30–0.45 (8H, m, 4!
H
2
3
1.62–1.68 (2H, m, CH CH COH), 2.29–2.35 (6H, m, 2!
CH C]CH , 2!OH), 4.84, 4.93 (2H, 2s, H C]C); d
CH ), 32.5 (CH CH COH), 38.0 (2!CH CH O), 41.7
3 2 2 2 2
(CH CH COH), 48.9 (CCH C), 63.8 (2!CH CH O),
2 2 2 2 2
2
2
2
2
2
C
K0.3, 1.0 (4!CH CH), 19.1 (2!CH), 29.2 (2!CH ), 32.3
2
68.5, 70.8 (2!COH), 114.1 (H C]C), 145.9 (C]CH );
2 2
3
C
(
CH CH COH), 42.0 (CH CH COH), 48.2 (CCH C), 70.2,
2
m/z 210 (M K18, !1%), 119 (12), 110 (32), 101 (46), 96
(10), 95 (100), 81 (13), 71 (28), 68 (23). HRMS calcd for
C H O 228.1725, found 228.1723.
2
2
2
2
7
(
(
1.0 (2!COH), 113.2 (H C]C), 147.2 (C]CH ); m/z 220
2 2
C
M K18, 1%), 117 (14), 111 (100), 105 (11), 95 (12), 91
17), 69 (98), 59 (18), 55 (23), 53 (11), 43 (54), 41 (99).
1
3 24 2
C
HRMS calcd for C H O 238.1933, (M KH O)
1
5.2.8. 5-(4-Hydroxy-1-propyl-4-piperidylmethyl)-2-
methyl-5-hexen-2-ol (2l). Colourless oil; t 14.55; R 0.30
5
26
2
2
2
20.1827, found 220.1804.
r
f
(
MeOH/EtOAc 1:1); n (film) 3373 (OH), 1638 (C]CH),
K1
5.2.4. 2-[3-(2-Hydroxy-2-adamantylmethyl)-3-butenyl]-
adamantan-2-ol (2g). Colourless solid; R 0.53 (hexane/
1134 cm (CO); d 0.91 (3H, t, JZ7.3 Hz, CH CH ), 1.23
H 3 2
(6H, m, 2!CH C), 1.45–1.85 (8H, m, CH CH COH, 2!
3 2 2
f
EtOAc 8:2); mp 69–70 8C; n (film) 3340 (OH), 1639
(
CH CH N, CH CH ), 2.03 (2H, s, 2!OH), 2.15–2.23 (4H,
2 2 2 3
m, 2!CH C]CH ), 2.35–2.45, 2.75–2.85 (6H, 2m, 3!
2 2
K1
C]CH), 1028 cm (CO); d 1.45–2.25 (34H, m, 8!CH,
H
1
H C]C); d 27.0, 27.2, 27.4, 29.6, 36.9, 37.5, 38.4, 40.7
3!CH ), 2.47 (2H, s, 2!OH), 4.83, 4.97 (2H, 2s,
CH N), 4.82, 4.97 (2H, 2s, H C]C); d 11.9 (CH CH ),
2 2 C 3 2
19.5 (CH CH ), 29.3 (2!CH ), 32.5 (CH CH COH), 36.8
2 3 3 2 2
2
2
C
(
3
4
(
8!CH), 30.6, 32.9, 33.1, 33.9, 34.6, 34.8, 35.0, 36.1, 37.0,
7.8, 38.3 (10!CH CH, CH CH CO), 41.1 (CH CH CO)
(2!CH CH N), 41.8 (CH CH OH), 49.1 (CCH C), 60.2
2 2 2 2 2
(3!CH N), 68.8, 70.8 (2!COH), 114.0 (H C]C), 146.2
2 2
2
2
2
2
2
C
(C]CH ); m/z 269 (M , 2%), 240 (23), 222 (21), 142 (17),
7.9 (CCH C), 74.3, 74.8 (2!CO), 114.0 (H C]C), 147.9
2
2
2
C
C]CH ); m/z 352 (M K18, O1%), 152 (11), 151 (100),
140 (61), 124 (12), 112 (25), 98 (13), 72 (20), 70 (16), 59
(18), 57 (14), 56 (25), 55 (22), 44 (21), 43 (85), 42 (100), 41
(50). HRMS calcd for C H NO 269.2355, found
2
1
50 (36), 148 (16), 116 (11), 107 (13), 105 (10), 93 (17), 91
(
(
27), 81 (25), 80 (28), 79 (42), 77 (15), 67 (14), 55 (18), 53
10). Anal. calcd for C H O : C, 81.03; H, 10.34, found C,
1
6
31
2
269.2321.
2
5 38 2
8
0.95; H, 10.35.
5
.2.9.
5-(4-Hydroxytetrahydro-2H-4-thiopyranyl-
methyl)-2-methyl-5-hexen-2-ol (2m). Colourless oil; tr
5.2.5. 1-Cyclohexyl-6-methyl-3-methylideneheptane-1,6-
diol (2i). Colourless oil; t 13.65; R 0.40 (hexane/EtOAc
r
f
14.53; R 0.45 (hexane/EtOAc 1:1); n (film) 3385 (OH),
f
K1
:2); n (film) 3378 (OH), 1641 (C]CH), 1133 cm (CO);
K1
1637 (C]CH), 1127 cm (CO); d 1.24 (6H, m, 2!CH ),
8
d 1.00–1.80 [13H, m, CHCHOH, (CH ) , CH COH], 1.24
H
3
H
2 5
2
1.58–1.95 (6H, m, CH CH COH, 2!CH CH S), 1.95 (2H,
2
2
2
2
(
6H, s, 2!CH ), 1.85 (br s, 2!OH), 2.00–2.20 (3H, m,
3
br s, 2!OH), 2.18–2.22 (4H, m, 2!CH C]CH ), 2.40,
2 2
CH CH C]CH , CHCH H C), 2.31 (1H, d, JZ12.0 Hz,
2.44, (2H, 2m, 2!CH CH H S), 2.98 (2H, m, 2!
2 A B
2
2
2
A
B
CHCH H C), 3.48 (1H, ddd, JZ10.2, 5.6, 2.8 Hz, CHO),
CH CH H S), 4.80, 4.98 (2H, 2s, H C]C); d 24.2
2 A B 2 C
A
B
4
.86, 4.93 (2H, 2s, H C]C); d 26.2, 26.3, 26.5, 28.2, 29.1,
(2!CH S), 29.3 (2!CH ), 32.7 (CH CH COH), 38.6
2 3 2 2
2
C
2
CH COH), 41.6 (CHCOH), 43.5 (CCH CH), 70.9 (COH),
9.2 [(CH ) , CH CH COH], 30.3 (2!CH ), 41.5 (CH -
(2!CH CH S), 41.8 (CH CH COH), 49.2 (CCH C), 69.6,
2 2 2 2 2
2
5
2
2
3
2
2
2
70.9 (2!COH), 114.3 (H C]C), 145.8 (C]CH ); m/z 244
2 2
C
7
2.8 (CHOH), 112.2 (H C]C), 147.5 (C]CH ); m/z 222
2
(M , 1%), 110 (31), 99 (23), 95 (86), 88 (19), 87 (10), 83
(29), 81 (15), 79 (10), 71 (17), 69 (16), 68 (39), 67 (19), 61
(22), 60 (14), 59 (48), 55 (69), 53 (26), 47 (24), 46 (13), 45
(27), 44 (14), 43 (100), 42 (12), 41 (67), 40 (15). HRMS
calcd for C H O S 244.1497, found 244.1492.
2
C
(M K18, !1%), 113 (11), 110 (21), 95 (100), 83 (12), 81
(15), 69 (14), 68 (29), 67 (21), 59 (30), 55 (48), 53 (11),
4
3 (48), 41 (64). HRMS calcd for C H O 240.2089,
15 28 2
C
(
M KH O) 222.1984, found 222.1987.
2
13 24 2
5
phenyl)heptane-1,6-diol (2j). Colourless oil; t 17.63; Rf
.2.6.
6-Methyl-3-methylene-1-(3,4,5-trimethoxy-
5.2.10. 4-[2-(4-Hydroxytetrahydro-2H-4-thiopyranyl)-
ethyl]allyl-1-propylpiperidin-4-ol (2n). Colourless oil; tr
20.18; R 0.38 (MeOH/EtOAc 1:1); n (film) 3385 (OH),
r
0
1
1
2
.33 (MeOH/EtOAc 1:1); n (film) 3394 (OH), 1595, 1507,
f
K1
630 (C]CH), 1127 cm (CO); d 1.25 (6H, s, 2!CH ),
K1
H
3
1638 cm (C]CH); d 0.90 (3H, t, JZ7.3 Hz, CH CH ,),
H
3
2
.60–1.70 (2H, m, CH COH), 1.90–2.20 (6H, m, 2!OH,
2
1.45–1.90 (12H, m, CH CH COH, 3!CH CH N, 2!
CH CH S), 2.05 (2H, s, 2!OH), 2.18–2.23 (4H, m, 2!
2 2
2 2 2 2
!CH C]CH ), 3.83, 3.88 (9H, 2s, 3!CH O), 4.75–4.85
2
2
3
(
1H, m, CHO), 4.94, 4.97 (2H, 2s, CH ZC), 6.61 (2H, s,
CH C]CH ), 2.37–2.47 (2H, br dt, 2!CH H S), 2.25–
2 2 A B
2
2
!ArH); dC 29.3 (2!CH ), 30.4 (CH CH COH), 41.5
2.35, 2.65–2.75 (6H, 2m, 3!CH N), 2.90–3.00 (2H, td, JZ
3
2
2
2
(
(
(
CH CH), 46.9 (CH COH), 56.1, 60.8 (3!CH O), 70.9
2
12.5, 2.8 Hz, 2!CH H S), 4.81, 4.96 (2H, 2s, H C]C);
d 12.0 (CH CH ), 20.0 (CH CH ), 24.3 (2!CH S), 30.6
C 3 2 2 3 2
2
3
A
B
2
COH), 72.0 (CHOH), 102.7, 103.6 (2!ArCH), 112.7
H C]C), 139.7, 139.8, 153.2 (4!ArC), 146.6 (C]CH );
2
2
(CCH CH COH), 37.2, 38.3 (2!CH CH N, 2!
2
2
2
2
C
m/z 324 (M , !1%), 198 (11), 197 (100), 196 (25), 181
10), 169 (44), 154 (16), 138 (17). HRMS calcd for
C H O 324.1937, found 324.1928.
CH CH S), 41.4 (CCH CH COH), 49.5 (CCH C), 60.4,
2 2 2 2 2
(
60.7 (3!CH N), 69.3, 69.9 (2!COH), 114.3 (H C]C),
2 2
C
146.0 (C]CH ); m/z 327 (M , 7%), 299 (20), 298 (99),
1
8
28
5
2
281 (37), 210 (10), 142 (20), 141 (15), 140 (100), 124 (12),
112 (27). HRMS calcd for C H NO S 327.2232, found
327.2230.
5.2.7. 5-(4-Hydroxytetrahydro-2H-4-pyranylmethyl)-2-
methyl-5-hexen-2-ol (2k). Colourless oil; t 12.65; R 0.43
1
8
33
2
r
f

3446
F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
5.2.11. 1,1-Dicyclopropyl-3-[(1R*,2S*)-2-hydroxycyclo-
hexylmethyl)]-3-buten-1-ol (2o). Colourless oil; t 14.95;
13.2 Hz, CCH C), 3.64, 3.73 (2H, AB system, JZ9.0 Hz,
2
CH O); d 8.4, 8.5 (2!CH CH ), 28.9, 29.1, (2!CH C),
29.6, 30.0 (2!CH CH ), 37.0, 38.8, (CH CH ), 48.7
2 3 2 2
r
2
C
3
2
3
R 0.40 (hexane/EtOAc 8:2); n (film) 3360 (OH), 3083
f
K1
(
0
cyclopropyl C–H), 1638 (C]CH), 1024 cm
(CO); dH
.25–0.50 (8H, m, 4!cyclopropyl CH ), 0.75–0.95 (2H, m,
(CCH C), 76.6 (CH O), 80.7, 85.7, 89.5 (3!C); m/z 183
2 2
C
(M K29, 57%), 165 (10), 153 (32), 109 (57), 101 (12), 97
(17), 93(25), 84(15), 83(21), 73(18), 71(11), 70(29), 69(43),
67 (12), 57 (100), 56 (29), 55 (66), 53 (13), 43 (81), 42 (15), 41
(85). HRMS calcd for C H O 183.1385, found 183.1381.
2
2
!cyclopropyl CH), 1.15–2.10 [12H, m, 2!OH, CH2-
CHCHOH, (CH ) ], 2.30, 2.39 (2H, AB system, JZ
2
4
1
3.6 Hz, CCH C), 2.74 (1H, dd, JZ13.9, 4.2 Hz,
2
13 24 2
CHCHOH), 3.25 (1H, td, JZ5.5, 4.2 Hz, CHOH), 4.87,
.93 (2H, 2s, H C]C); dC K0.3, K0.2, 0.9, 1.0 (4!
cyclopropyl CH ), 18.9, 19.1 (2!cyclopropyl CH), 24.8,
4
5.3.2. 8,8-Diethyl-2,2-dipentyl-1,7-dioxaspiro[4.4]no-
nane (3b). Colourless oil; t 15.07; R 0.59 (hexane/
2
2
r
f
K1
2
5.5, 30.8, 35.5, 41.5 [(CH ) , CCH CH], 43.7 (CHCOH),
2
EtOAc 8:2); n (film) 1453, 1060 cm
(CO); dH 0.75–
4
2
4
7.6 (CCH C), 70.8 (COH), 75.2 (CHOH), 115.3
2
0.95 (12H, m, 4!CH ), 1.20–2.10 (24H, m, 4!CH CH ,
3 2 3
C
(
(
(
(
(
2
H C]C), 146.1 (C]CH ); m/z 246 (M K18, 1%), 160
8!CH CH ), 1.74, 1.99 (2H, AB system, JZ13.1 Hz,
2
2
2 2
16), 145 (22), 120 (36), 119 (12), 117 (22), 111 (12), 105
36), 92 (10), 91 (39), 79 (24), 77 (20), 69 (22), 67 (14), 65
13), 57 (18), 55 (25), 53 (19), 51 (10), 43 (23), 41 (100), 40
11). HRMS calcd for C H O 264.2089, (M KH O)
46.1984, found 246.1980.
CCH C), 3.61, 3.72 (2H, AB system, JZ8.9 Hz, CH O); d
2 2 C
8.5, 14.0 (4!CH ), 22.6, 24.0, 24.1, 29.4, 29.6, 30.1, 32.5,
32.6, 35.5, 36.9, 39.2, 39.5 (4!CH CH , 8!CH CH ),
3
2
3
2
2
C
1
7
28
2
2
48.4 (CCH C), 77.2 (CH O), 85.5, 85.7, 89.1 (3!C); m/z
2 2
C
295 (M K29, 22%), 253 (29), 139 (21), 121 (45), 109 (21),
01 (21), 99 (11), 97 (19), 95 (14), 83 (20), 81 (13), 71 (20),
69 (29), 67 (15), 57 (100), 56 (18), 55 (77), 43 (94), 42 (10),
1
5
.2.12. 4-[2-(1R*,2S*)-(2-Hydroxycyclohexylmethyl)-
C
allyl]tetrahydro-2H-pyran-4-ol (2q). Colourless oil; tr
5.68; Rf 0.30 (EtOAc); n (film) 3441 (OH), 1641
41 (84). HRMS calcd for C H O 324.3028, (M KC H )
2 5
21
40
2
1
295.2637, found 295.2638.
K1
(
(
C]CH), 1106 cm
CH ) , CH CHCHOH, 2!CH CH O), 2.22, 2.27 (2H,
(CO); dH 1.15–2.05 (14H, m,
2
4
2
2
2
5.3.3. (2R*,5R*) and (2R*,5S*)-8,8-Diethyl-2-hexyl-1,7-
dioxaspiro[4.4]nonane (3c). Colourless oil; t 13.38; R
f
AB system, JZ13.6 Hz, CCH C), 2.32 (2H, br s, 2!OH),
2
r
K1
2
5
4
4
4
.69 (1H, dd, JZ13.9, 4.2 Hz, CHCHOH), 3.24 (1H, td, JZ
.5, 4.2 Hz, CHOH), 3.73–3.80 (4H, m, 2!CH O), 4.85–
.97 (2H, 2s, CH ]C); d 24.9, 25.5, 30.9, 35.7, 37.7, 38.6,
0.50 (hexane/EtOAc 8:2); n (film) 1459, 1060 cm (CO);
d 0.75–1.00 (18H, m, 6!CH ), 1.15–2.10 (40H, m, 6!
2
H
3
2
C
CH CH , 12!CH CH , 2!CCH C), 3.40–3.45 (1H, m,
2 3 2 2 2
CH minor diastereoisomer), 3.61, 3.76 (2H, AB system, JZ
1.8 [CCH CH, 2!CH CH O, (CH ) ], 43.4 (CHCHOH),
2 4
2
2
2
8.3 (CCH C), 64.0 (2!CH O), 68.7 (COH), 75.3
2
9.1 Hz, CH O minor diastereoisomer), 3.63, 3.80 (2H, AB
system, JZ9.1 Hz, CH O major diastereoisomer), 3.75–
2
2
(
(
CHOH), 115.8 (H C]C), 144.7 (C]CH ); m/z 236
2
2
2
C
M K18, !1%), 136 (23), 121 (68), 107 (21), 101 (48),
3.90 (1H, m, CH major diastereoisomer); d 8.5, 13.4 (6!
C
9
8
9 (11), 98 (85), 95 (14), 94 (37), 93 (35), 91 (13), 83 (21),
1 (68), 80 (28), 79 (37), 77 (13), 71 (45), 69 (11), 68
CH ), 22.5, 26.0, 29.3, 29.4, 29.7, 29.8, 30.0, 31.3, 31.6,
3
31.7, 34.9, 36.2, 36.3 (6!CH CH , 12!CH CH ), 47.4,
2
3
2
2
(
(
(
11), 67 (30), 57 (21), 55 (52), 54 (10), 53 (52), 43 (80), 42
22), 41 (100). HRMS calcd for C H O 254.1882,
48.1 (2!CCH C), 76.0, 76.6 (2!CH), 78.8, 79.0 (2!
2
C
CH O), 85.9, 86.0, 89.4 (4!C); m/z 239 (M K29, 33%),
1
5
26
3
2
C
M KH O) 236.1776, found 236.1786.
2
221 (10), 109 (11), 83 (20), 69 (12), 57 (90), 55 (63), 43
(
72), 41 (100). HRMS calcd for C H O 268.2402,
17 32 2
C
5
.3. General procedure for the preparation of 1,7-
(M KC H ) 239.2011, found 239.1992.
2 5
dioxaspiro[4.4]nonanes 3. Isolation of iodohydrins 4g
and 4i
5.3.4. (2R*,5R*) and (2R*,5S*)-8,8-Diethyl-2-phenyl-1,7-
dioxaspiro[4.4]nonane (3d). Colourless oil; t 14.08, 14.40;
r
K1
Iodine (0.382 g, 1.5 mmol) was added to a solution of the
corresponding diol 2 (1 mmol) in THF (20 ml) (dioxane/
Rf 0.61, 0.63 (hexane/EtOAc 8:2); n (film) 1459, 1060 cm
(CO); d 0.75–0.95 (12H, m, 4!CH ), 1.20–2.40 (20H, m,
H
3
H O 7:1 was used for diols 2l–n). The mixture was stirred
2
4!CH CH , 2!CH CH , 2!CCH C), 3.70, 3.93 (2H, AB
2 3 2 2 2
for 5 min at room temperature and then Ag O (0.346 g,
2
system, JZ9.1 Hz, CH O), 3.75, 3.98 (2H, AB system, JZ
2
1
.5 mmol) was added with additional stirring for 24 h. The
9.5 Hz, CH O), 4.20, 4.93 (2H, 2t, JZ8.9 Hz, CHPh), 7.20–
2
resulting suspension was filtered and water (10 ml) was
added to the filtrate, followed by extraction with ethyl
acetate (3!10 ml). The organic phase was successively
washed with a saturated solution of Na SO (2!10 ml)
and water (2!10 ml), and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure
7.40 (10H, m, 10!ArH); d 8.5, 8.55, 8.6, 8.65 (4!CH ),
29.7, 29.8, 29.9, 35.0, 35.1, 42.8, 45.0, 46.0 (4!CH CH ,
C
3
2
3
2!CH CH ), 48.4 (2!CCH C), 77.2 (2!CH O), 80.4
2
2
2
2
(2!CHO), 86.3, 86.7, 90.5, 90.8 (4!C); m/z (t 14.08) 231
r
2
3
C
(M K29, 52%), 129 (10), 109 (28), 105 (17), 104 (65), 91
(21), 77 (10), 57 (100), 55 (33), 53 (10), 43 (24), 41 (28), 40
(11); m/z (t 14.40) 231 (M K29, 30%), 91 (16), 83 (20), 57
C
(
15 Torr) to furnish pure compounds 3. Compound 3g
r
needed purification by column chromatography (silica gel,
hexane/EtOAc).
(100), 55 (24), 43 (12), 41 (15). HRMS calcd for C H O
7 24 2
1
C
260.1776, (M KC H ) 231.3102, found 231.3100.
2
5
5.3.1. 8,8-Diethyl-2,2-dimethyl-1,7-dioxaspiro[4.4]no-
nane (3a). Colourless oil; t 9.34; R 0.50 (hexane/EtOAc
5.3.5. 8,8-Dicyclopropyl-2,2-dimethyl-1,7-dioxaspiro-
[4.4]nonane (3e). Colourless oil; tr 15.07; Rf 0.65
(hexane/EtOAc 8:2); n (film) 3060 (cyclopropyl C–H),
1054 cm (CO); dH 0.30–0.50 (8H, m, 4!CH CH),
2
0.80–0.95, 1.00–1.15 (2H, 2m, 2!CH), 1.20, 1.24 (6H, 2s,
r
K1
f
8
2
1
:2); n (film) 1461, 1056 cm (CO); d 0.80–0.88 (6H, m,
H
K1
!CH CH ), 1.20–1.30 (10H, m, 2!CH CH , 2!CCH ),
3
2
2
3
3
.35–2.15 (4H, CH CH ), 1.75, 1.98 (2H, AB system, JZ
2
2

F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
3447
2
1
!CH ), 1.70–1.85, 1.95–2.15 (4H, 2m, CH CH ), 1.76,
3
(2!C), 89.7 (CHO), 102.6 (2!ArCH), 138.1, 153.3 (4!
ArC); m/z 322 (M , 85%), 251 (15), 221 (12), 211 (16), 195
2
2
C
.98 (2H, AB system, JZ13.3 Hz, CCH C), 3.60, 3.73 (2H,
2
AB system, JZ8.7 Hz, CH O); d 0.5, 0.6, 1.3, 1.5 (4!
(60), 194 (23), 182 (13), 181 (100), 179 (27). HRMS calcd
for C H O 322.1780, found 322.1767.
2
C
CH CH), 18.8, 19.1 (2!CH), 28.9, 29.1 (2!CH ), 36.7,
3
2
3
18 26 5
8.8 (CH CH ), 48.1 (CCH C), 77.7 (CH O), 80.7, 83.4,
2 2 2 2
C
0
5.3.10. 2,2-Dimethyldispiro[tetrahydrofuran-5,4 -tetra-
hydrofuran-2 ,4 -tetrahydro-2H-pyran] (3k). Colourless
8
(
(
9.1 (3!C); m/z 236 (M , !1%), 195 (67), 121 (13), 109
12), 93 (10), 79 (13), 69 (65), 67 (14), 55 (40), 43 (90), 41
0
00
C
100). HRMS calcd for C H O 236.1776, (M KC H )
K1
1
5
24
2
3
5
oil; t 11.48; R 0.34 (hexane/EtOAc 1:1); n (film) 1051 cm
r
f
1
95.1395, found 195.1404.
(CO); d 1.22, 1.24 (6H, 2s, 2!CH ), 1.60–2.10 (8H, m,
H 3
2
!CH CH O, CCH CH C), 1.77, 2.08 (2H, AB system,
2 2 2 2
0
0
00
0
furan-5 ,4 -tetrahydrofuran] (3f). Colourless oil; t 16.28;
5
.3.6. 2 ,2 -Diethyldispiro[adamantane-2,2 -tetrahydro-
JZ13.0 Hz, CCH C), 3.56–3.65, 3.77–3.86 (4H, 2m, 2!
CH CH O), 3.61, 3.72 (2H, AB system, JZ9.2 Hz, CH O);
dC 29.0, 29.1 (2!CH ), 36.3, 37.2, 37.9, 38.7 (2!
CH CH O, CCH CH C), 51.0 (CCH C), 65.1, 65.2 (2!
2
0
00
Rf 0.75 (hexane/EtOAc 8:2); n (film) 1460, 1061 cm
r
2
2
2
K1
3
(
CO); d 0.70–0.85 (6H, m, 2!CH ), 1.15–2.10 (24H, m,
3
H
2
2
2
2
2
2
!CH CH , CCH C, CCH CH C, 4!CHCH , 5!
2
CH CH O), 77.2 (CCH O), 79.4, 81.1, 89.2 (3!C); m/z
2 2 2
3
2
2
2
2
C
CH CH), 3.62, 3.74 (2H, AB system, JZ8.9 Hz, CH O);
226 (M , 10%), 140 (15), 125 (14), 122 (28), 115 (52), 112
(17), 97 (12), 95 (13), 83 (53), 81 (13), 70 (40), 69 (25), 68
(16), 67 (22), 57 (14), 56 (33), 55 (45), 53 (27), 43 (100), 42
(27), 41 (91), 40 (23). HRMS calcd for C H O 295.1569,
2
2
d 8.6, 8.7 (2!CH ), 27.2, 27.4, 36.1, 37.8, (4!CH), 31.3,
C
3
32.9, 33.2, 33.3, 34.4, 35.3, 35.9, 37.0, 37.7 (5!CH CH,
2
CH CH , 2!CH CH ), 49.5 (CCH C), 75.7 (CH O), 85.9,
2
2
2
3
2
2
13 22 3
C
86.2, 89.2 (3!C); m/z 304 (M , !1%), 276 (13), 275 (71),
203 (34), 190 (11), 175 (12), 166 (11), 135 (99), 151 (41),
149 (16), 148 (15), 135 (38), 133 (10), 121 (11), 105 (14), 97
found 226.1571.
0
0
00
0
5.3.11. 2 ,2 -Dimethyl-1-propyldispiro[piperidine-4,2 -
0
00
(
(
(
10), 95 (11), 93 (24), 92 (13), 91 (38), 81 (19), 80 (12), 79
44), 77 (17), 69 (21), 67 (32), 65 (10), 57 (84), 55 (100), 53
22), 43 (44), 42 (11), 41 (95). HRMS calcd for C H O
tetrahydrofuran-4 ,5 -tetrahydrofuran] (3l). Colourless
oil; t 14.01; R 0.25 (EtOAc/MeOH 1:1); n (film) 1057
r
f
2
0
32
2
(CO); d 0.92 (3H, t, JZ7.4 Hz, CH CH ), 1.20, 1.22 (6H,
H 3 2
C
3
04.2402, (M KC H ) 275.2011, found 275.2015.
2
2s, 2!CCH ), 1.40–2.10 (10H, m, CCH CH C, 2!
3 2 2
5
CH CH N, CH CH ), 1.73, 2.07 (2H, AB system, JZ
2
2
2
3
0
0
00
tetrahydrofuran-2 ,2 -adamantane] (3g). Colourless
5
.3.7. Dispiro[adamantane-2,2 -tetrahydrofuran-5 ,4 -
13.0 Hz, CCH C), 2.35–2.45, 2.70–2.80 (6H, 2m, 3!
CH N), 3.63, 3.75 (2H, AB system, JZ9.2 Hz, CH O); d
2
0
0
000
2
2
C
solid; R 0.67 (hexane/EtOAc 8:2); mp 48–49 8C; n (film)
f
12.1 (CH CH ), 19.4 (CH CH ), 28.7, 29.0 (2!CH C),
3 2 2 3 3
35.5, 36.1, 37.3, 37.5 (2!CH CH N, CCH CH C), 43.8
2 2 2 2
K1
1
1
469, 1065 cm
(CO); dH 1.40–2.28 (34H, m, 8!CH,
0!CH CH, CH CH , CCH C), 3.66, 3.77 (2H, AB
(NCH CH CH ), 51.3 (CCH C), 60.1, 60.2 (2!NCH CH -
2 2 3 2 2 2
2
2
2
2
C
C), 77.0 (CH O), 80.0, 81.1, 81.9 (3!C); m/z 267 (M ,
system, JZ8.9 Hz, CH O); d 26.8, 27.1, 27.2, 27.3, 35.7,
2
C
2
3
3
4
3
8.0, 38.3, 38.8 (8!CH), 33.0, 33.4, 33.5, 33.7, 35.2, 35.5,
5.7, 35.8, 35.9, 36.3, 37.8, 37.9 (10!CH CH, CH CH ),
3%), 239 (17), 238 (100), 110 (10). HRMS calcd for
C H NO 267.2198, found 267.2198.
2
2
2
16 29
2
9.7 (CCH C), 76.5 (CH O), 86.3, 86.6, 88.7 (3!C); m/z
2
2
C
68 (M , 2%), 338 (10), 206 (15), 205 (100), 204 (11), 165
0
5.3.12. 2,2-Dimethyldispiro[tetrahydrofuran-5,4 -tetra-
0
Colourless oil; t 13.46; R 0.35 (hexane/EtOAc 7:3); n
00
(
28), 151 (15), 91 (12), 79 (15). HRMS calcd for C H O
36 2
hydrofuran-2 ,4 -tetrahydro-2H-thiopyran]
(3m).
2
5
3
68.2715, found 368.2711.
r
K1
f
(film) 1021 cm
(CO); dH 1.22, 1.26 (6H, 2s, 2!CH3),
0
0
00
5
.3.8. Trispiro[cyclohexane-1,2 -tetrahydrofuran-5 ,4 -
1.60–2.10 (8H, m, 2!CH CH S, CCH CH C), 1.78, 2.07
2 2 2 2
0
0
000
tetrahydrofuran-2 ,1 -cyclohexane] (3h). Colourless
oil; t 14.45; R 0.45 (hexane/EtOAc 8:2); n (film) 1459,
(2H, AB system, JZ13.6 Hz, CCH C), 2.25–2.50, 2.75–
2
2.90 (4H, 2m, 2!CH CH S), 3.69, 3.79 (2H, AB system,
JZ9.2 Hz, CH O); d 25.4, 26.2 (2!CH CH S), 29.0, 29.1
r
f
2
2
K1
1
1
061 cm
.72, 2.01 (2H, AB system, JZ12.8 Hz, CCH C), 3.65, 3.76
(CO); dH 1.20–2.10 (24H, m, 12!CH CH ),
2
2
2 C 2 2
(2!CH ), 35.7, 38.7, 42.5, 42.6 (2!CH CH S, CCH CH -
3 2 2 2 2
2
(
2
2H, AB system, JZ8.9 Hz, CH O); d 23.5, 23.8, 23.9,
C), 52.5 (CCH C), 77.2 (CH O), 79.0, 81.4, 89.3 (3!C);
2 2
2
C
C
5.5, 25.6, 35.9, 36.1, 37.9, 38.3, 38.7 (12!CH CH ), 50.3
m/z 242 (M , !1%), 227 (10), 209 (11), 140 (21), 125 (15),
110 (35), 99 (45), 98 (43), 97 (41), 83 (51), 81 (11), 70 (41),
67 (22), 57 (14), 53 (12), 44 (10), 43 (100), 42 (17). HRMS
2
2
(
(
1
CCH C), 76.3 (CH O), 82.6, 82.8, 88.6 (3!C); m/z 264
2 2
C
M , 14%), 221 (12), 165 (11), 155 (14), 152 (25), 151 (14),
33 (15), 125 (13), 113 (71), 109 (12), 97 (20), 96 (14), 95
C
calcd for C H O S 242.1341, (M KCH ) 227.1106,
1
3
22
2
3
(
(
(
33), 94 (19), 91 (12), 81 (36), 79 (27), 69 (17), 67 (50), 57
10), 55 (81), 54 (24), 53 (22), 43 (40), 42 (22), 41 (100), 40
18). HRMS calcd for C H O 264.2089, found 264.2122.
found 227.1104.
0
1
7 28 2
5.3.13. 1-Propyltrispiro[piperidine-4,2 -tetrahydro-
0
00
00 000
furan-4 ,2 -tetrahydrofuran-5 ,4 -tetrahydro-2H-thyo-
pyran] (3n). Colourless oil; t 18.51; R 0.10 (EtOAc); n
5.3.9. 2,2-Dimethyl-8-(3,4,5-trimethoxyphenyl)-1,7-
dioxaspiro[4.4]nonane (3j) (major diastereoisomer).
Colourless oil; t 17.21; R 0.55 (EtOAc); n (film) 1591,
r
1
CH ), 1.70–2.20 (6H, m, CH CH , CH CH), 3.83, 3.86 (9H,
r
f
K1
(film) 1045 cm
CH CH ), 1.40–2.10 (14H, m, CH CH , 2!CH CH N,
(CO); dH 0.87 (3H, t, JZ7.4 Hz,
f
3
2
2
3
2
2
K1
506 (C]CH), 1127 cm (CO); d 1.27, 1.31 (6H, 2s, 2!
2!CH CH S, CCH CH C), 1.70, 2.05 (2H, AB system,
2 2 2 2
JZ12.8 Hz, CCH C) 2.20–2.75 (10H, 2!CH S, 3!
H
3
2
2
2
2
2
2
s, 3!CH O), 3.84, 3.87 (2H, AB system, JZ9.0 Hz,
CH N), 3.60, 3.73 (2H, AB system, JZ9.3 Hz, CH O);d
2 2 C
3
CH O), 5.04 (1H, dd, JZ10.1, 5.9 Hz, CHO), 6.57 (2H, s,
11.8 (CH CH ), 22.5 (CH CH ), 24.1, 24.3 (2!CH S),
33.3, 35.2, 37.1, 37.5, 38.0, 38.1 (CCH CH C, 2!
2 2
2
3 2 2 3 2
2
!ArH); dC 29.1 (2!CH ), 35.0, 37.7 (CH CH ), 48.8
3
2
2
(
CH CH), 56.1, 60.8 (3!CH O), 77.2 (CH O), 79.5, 80.8
3
CH CH N, 2!CH CH S), 49.9, 50.8 (NCH CH CH ,
2 2 2 2 2 2 3
2
2

3448
F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
CCH C), 58.3, 59.0 (2!NCH CH C), 76.8 (CH O), 82.2,
2
8
(3q). Colourless oil; t 14.59; R 0.34 (hexane/EtOAc 1:1); n
r f
2
2
2
C
2.4, 84.3 (3!C); m/z 325 (M , !1%), 296 (100), 282
K1
(film) 1055 cm
CH CH CO, (CH ) , CCH CH, CHCHO], 1.80, 2.07 (2H,
(CO); dH 1.00–2.20 [15H, m, 2!
(
(
30), 142 (12), 141 (70), 140 (12), 124 (23), 123 (10), 112
29), 44 (36), 43 (20), 42 (20), 41 (11). HRMS calcd for
2
2
2 4
2
AB system, JZ13.3 Hz, CCH C), 3.04 (1H, td, JZ10.1,
2
C H NO S 325.2075, found 325.2070.
2
3.7 Hz, CHO), 3.60–3.90 (4H, m, 2!CH CH O), 3.67, 3.93
1
8
31
2
2
(
2H, AB system, JZ9.5 Hz, CH O); d 24.2, 25.6, 28.9,
2 C
0
0
31.1, 31.5, 37.9, 40.0 [(CH ) , CCH CH, CH CH O], 45.3
2 4 2 2 2
(CHCHO), 51.6 (CCH C), 65.1, 67.3 (CH CH O), 76.4
2 2 2
5
.3.14. (2R*,3aS*,7aR*) and (2R*,3aR*,7aS*)-2 ,2 -Di-
0
cyclopropylspiro[perhydrobenzo[b]furan-2,4 -tetra-
hydrofuran] (3o). Colourless oil; t 14.65; R 0.40 (hexane/
EtOAc 8:2); n (film) 3053 (cyclopropyl C–H), 1063 cm
CO); dH 0.25–0.50 (16H, m, 8!cyclopropyl CH CH),
.75–1.00 (4H, m, 4!cyclopropyl CH), 1.05–2.20 [26H, m,
!(CH ) , 2!CCH CH, 2!CHCHO, 2!CCH C], 3.00
1H, td, JZ10.0, 3.8 Hz, CHO major diastereoisomer),
.05–3.15 (1H, m, CHO minor diastereoisomer), 3.48, 3.76
2H, AB system, JZ8.9 Hz, CH O minor diastereoisomer),
(
(
1
CH O), 79.9, 88.2 (2!C), 83.3 (CHO); m/z (t 14.59) 252
2 r
M , 4%), 208 (10), 155 (12), 154 (13), 122 (14), 107 (21),
15 (17), 108 (17), 99 (17), 98 (14), 97 (11), 96 (19), 95
r
f
C
K1
(
0
2
(
3
2
(
(
(
23), 94 (12), 83 (34), 82 (16), 81 (43), 80 (10), 79 (20), 70
12), 69 (14), 68 (24), 67 (58), 57 (14), 55 (53), 54 (22), 53
33), 43 (49), 42 (24), 41 (100), 40 (25). HRMS calcd for
2
4
2
2
C H O 252.1725, found 252.1724.
15 24 3
(
2
3
diastereoisomer); d K0.4, 0.1, 0.3, 0.6, 1.0, 1.2, 1.3, 1.4
.59, 3.87 (2H, AB system, JZ9.2 Hz, CH O major
2
C
(
8!cyclopropyl CH CH), 18.5, 18.8, 19.0, 19.3 (4!
2
cyclopropyl CH), 24.3, 25.4, 25.8, 28.8, 29.0, 29.4, 31.4,
1.5, 40.0, 40.6 [2!(CH ) , 2!CCH CH], 45.4, 45.7 (2!
CHCHO), 48.3, 48.9 (2!CCH C), 78.1, 78.4 (2!CH O),
3
2
4
2
2
2
8
2.8, 83.2 (2!CHO), 84.1, 84.3, 87.9, 88.2 (4!C); m/z 262
C
(
M , !1%), 222 (15), 221 (100), 121 (11), 95 (10), 81 (11),
0
methylspiro[adamantane-2,2 -tetrahydrofuran] (4g).
0
5
.3.17. 5 -(2-Hydroxy-2-adamantylmethyl)-5 -iodo-
7
4
9 (13), 69 (14), 67 (11), 57 (17), 55 (55), 54 (25), 53 (35),
4 (10), 43 (79), 42 (27), 41 (100), 40 (27). HRMS calcd for
0
Colourless oil; R 0.60 (hexane/EtOAc 8:2); n (film) 3444
f
K1
C H O 262.1933, found 262.1931.
1
7
26
2
(OH), 1100 cm
1
(CO); dH 1.20–2.20 (35H, m, 8!CH,
0!CH CH, OH, CCH CH C, CCH C), 3.33, 3.51 (2H,
2 2 2 2
AB system, JZ9.8 Hz, CH I); d 15.1 (CH I), 26.2, 26.3,
2
C
2
2
3
(
7.3, 27.4, 29.4, 36.3, 37.4, 39.1 (8!CH), 31.0, 31.7, 31.8,
2.4, 32.9, 33.0, 33.3, 33.5, 34.4, 34.7, 38.4, 40.0, 42.5
10!CH CH, CCH C, CCH CH C), 74.0, 78.1, 82.5 (3!
2 2 2 2
C
C); m/z 368 (M K128, !1%), 338 (10), 206 (10), 205
100), 151 (10), 79 (11), 127 (25), 126 (45), 43 (22), 42 (13).
HRMS calcd for C H IO 496.1838, (M KHI)
(
C
2
5
37
2
3
68.2715, found 368.2701.
00 00 00 0
.3.15. (2 R*,3a S*,7a R*)-Dispiro[cyclohexane-1,2 -
5
5.3.18. 1-Cyclohexyl-2-(2-iodomethyl-5,5-dimethyltetra-
hydro-2-furanyl)ethan-1-ol (4i). Colourless oil; t 12.52;
0
00
tetrahydrofuran-4 ,2 -perhydrobenzo[b]furan] (3p).
Colourless oil; t 14.33; R 0.43 (hexane/EtOAc 8:2); n
r
K1
r
f
Rf 0.62 (hexane/EtOAc 8:2); n (film) 3380 (OH), 1050 cm
(CO); d 0.98–2.00 [16H, m, (CH ) , CCH CH C, CHCH -
K1
(
CH CH , CCH CH, CHCHO), 1.76, 2.03 (2H, AB system,
film) 1447, 1064 cm (CO); d 1.20–2.10 (21H, m, 9!
H
H
2 5
2
2
A
2
2
2
H C, OH], 1.25, 1.28 (6H, 2s, 2!CH ), 2.23–2.35 (2H, 2m,
B 3
JZ13.2 Hz, CCH C), 3.02 (1H, td, JZ10.1, 3.6 Hz, CHO),
2
CHCH H C, CHCHOH), 3.19, 3.40 (2H, AB system, JZ
A B
3
.64, 3.90 (2H, AB system, JZ9.4 Hz, CH O); d 23.7,
2 C
10.2 Hz, CH I,), 3.55–3.60 (1H, m, CHOH); d 12.4 (CH I),
2 C 2
2
CH CH , CCH CH), 45.4 (CHCHO), 51.3 (CCH C), 76.2
3.8, 24.3, 25.4, 25.7, 29.0, 31.6, 37.3, 37.7, 40.6 (9!
2
6.2, 26.3, 26.6, 28.4, 28.6 [(CH ) ], 29.0, 29.5 (2!CH ),
2 5 3
2
2
2
2
37.5, 38.1 (CCH CH C), 41.1 (CHCH C), 44.0
2 2 2
C
(
1
(
8
5
CH O), 83.1 (CHO), 83.2, 88.4 (2!C); m/z 250 (M ,
2
(CHCHOH), 72.3 (CHOH), 84.3, 85.5 (2!C); m/z 238
6%), 221 (15), 207 (37), 155 (24), 154 (18), 152 (30), 119
16), 113 (12), 107 (22), 96 (10), 95 (24), 82 (15), 81 (57),
0 (14), 79 (22), 69 (11), 68 (10), 67 (47), 57 (11), 55 (74),
4 (20), 53 (27), 43 (37), 42 (19), 41 (100), 40 (16). HRMS
C
(
M K128, !1%), 155 (49), 127 (25), 126 (45), 125 (47),
1
6
4
13 (21), 97 (11), 95 (36), 93 (11), 83 (11), 81 (24), 70 (15),
9 (25), 67 (22), 57 (11), 56 (18), 55 (84), 54 (10), 53 (16),
3 (83), 42 (12), 41 (100). HRMS calcd for C H IO
2
1
5
27
calcd for C H O 250.1933, found 250.1963.
1
C
6
26
2
366.1056, (M KHI) 238.1933, found 238.1911.
5.4. General procedure for the oxidation of 1,7-
dioxaspiro[4.4]nonanes 3 to lactones 6
A suspension of RuO2 (21 mg, 0.16 mmol) and NaIO4
1.04 g, 4.88 mmol) in H O (5 ml) was added to a solution
(
of the corresponding 1,7-dioxaspiro[4.4]nonane
2
3
1.0 mmol) in CCl4 (5 ml) at room temperature. After
(
stirring the reaction for 24 h, Pr OH (3 ml) was added, the
resulting mixture being extracted with CCl (2!5 ml). The
4
i
5.3.16. (2R*,3aS*,7aR*)-Dispiro[perhydrobenzo[b]-
furan-2,4 -tetrahydrofuran-2 ,4 -tetrahydro-2H-pyran]
0
0
00

F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
3449
organic layer was dried over anhydrous sodium sulfate,
filtered, and evaporated under reduced pressure. The
resulting residue was passed through a pad containing
celite, in order to eliminate the remaining ruthenium
compounds, yielding the corresponding pure lactones 6,
which did not require any further purification.
38.0 (4!CH), 29.8, 30.0, 30.6, 32.0, 32.8, 34.5, 36.2, 37.1,
37.5 (5!CH CH, CCH CH C, 2!CH CH ), 46.1
(CCH C), 83.8, 87.4, 89.1 (3!C), 178.0 (C]O); m/z 289
(M K29, 18%), 274 (13), 246 (15), 245 (82), 177 (17), 175
(13), 149 (24), 107 (10), 105 (11), 98 (11), 97 (12), 95 (11),
93 (24), 92 (14), 91 (32), 84 (15), 81 (15), 80 (12), 79 (40),
2
2
2
2
3
2
C
7
5
7 (16), 69 (32), 67 (31), 57 (100), 56 (12), 55 (90), 54 (13),
3 (26), 44 (10), 43 (54), 42 (11), 41 (90), 40 (17). HRMS
5
.4.1. 8,8-Diethyl-2,2-dimethyl-1,7-dioxaspiro[4.4]no-
nan-6-one (6a). Colourless oil; t 11.05; R 0.31 (hexane/
C
r
f
calcd for C H O 318.2195 (M KCO ) 274.2297, found
20 30 3 2
K1
EtOAc 8:2); n (film) 1770 (C]O), 1050 cm (CO); dH
.80–0.95 (6H, m, 2!CH CH ), 1.21–1.29 (6H, m, 2!
274.2303.
.4.5. Trispiro[cyclohexane-1,2 -tetrahydrofuran-5 ,3 -
0
CH C), 1.35–1.40 (4H, m, 2!CH CH ), 1.35–2.25 (4H, m,
3
2
3
2
3
0
0
00
5
CH CH ), 2.05, 2.24 (2H, AB system, JZ13.7 Hz,
CCH C); d 7.7, 7.8 (2!CH CH ), 28.3, 28.9 (2!
CH CH ), 30.6, 30.7 (2!CH C), 37.2, 38.5 (CH CH ),
2
2
0
00 000
tetrahydrofuran-2 -one-5 ,1 -cyclohexane] (6h). Colour-
less oil; t 15.95; R 0.33 (hexane/EtOAc 8:2); n (film) 1770
2
C
3
2
r
f
2
3
3
2
2
(C]O); d 1.20–2.40 (24H, m, 12!CH CH ), 2.02, 2.25
2
4
2
1
6
4
5.1 (CCH C), 83.8, 84.1, 86.4 (3!C), 178.0 (C]O); m/z
2
H
2
C
11 (M K15, 1%), 169 (34), 154 (10), 153 (71), 139 (16),
(2H, AB system, JZ13.7 Hz, CH
23.9, 24.9, 25.5, 35.8, 36.1, 37.5, 37.6, 37.8, 38.0 (12!
C); d
22.5, 22.6, 23.7,
2
C
01 (12), 97 (35), 95 (10), 91 (11), 83 (37), 70 (31), 69 (47),
7 (10), 57 (78), 56 (41), 55 (50), 53 (15), 43 (100), 42 (18),
1 (76), 40 (12). HRMS calcd for C H O 226.1569,
CH ), 47.6 (CCH C), 83.3, 83.9, 85.8, (3!C), 177.8
2
2
C
(C]O); m/z 234 (M K44, 20%), 191 (14), 152 (17), 137
1
3 22 3
C
(
M KCH ) 211.1334, found 211.1339.
3
(10), 125 (39), 97 (27), 96 (12), 95 (32), 94 (36), 93 (16), 82
(14), 81 (41), 79 (22), 69 (14), 68 (13), 67 (38), 55 (88), 54
5.4.2. (2R*,5R*) and (2R*,5S*)-8,8-Diethyl-2-hexyl-1,7-
dioxaspiro[4.4]nonan-6-one (6c). Colourless oil; t 14.86;
(22), 53 (22), 44 (15), 43 (57), 42 (29), 41 (100), 40 (24).
HRMS calcd for C H O 278.1882, found 278.1879.
r
17 26 3
Rf 0.32 (hexane/EtOAc 8:2); n (film) 1774 (C]O),
1
K1
030 cm (CO); d 0.80–1.00 (18H, m, 6!CH ), 1.20–
H 3
0
0
5.4.6. (2R*,3aS*,7aR*) and (2R*,3aR*,7aS*)-4 ,4 -Di-
cyclopropyldispiro[perhydrobenzo[b]furan-2,3 -tetra-
2
.50 (36H, m, 12!CH CH , 6!CH CH ) 2.07, 2.25 (4H,
2
2
2
3
0
AB system, JZ14.0 Hz, 2!CCH C), 3.50–3.83 (2H, 2m,
2
0
hydrofuran-2 -one] (6o). Colourless oil; t 15.70; R 0.34
f
r
2
2
3
!CH); d 7.6, 7.7, 14.0, 14.05 (6!CH ), 22.4, 22.5, 23.7,
8.1, 28.8, 30.5, 30.6, 31.4, 31.5, 31.7, 35.6, 35.7, 35.8,
7.7, 42.8 (12!CH CH , 6!CH CH ), 44.3, 46.6 (2!
C 3
(
(
hexane/EtOAc 8:2); n (film) 3045 (cyclopropyl C–H), 1772
K1
C]O), 1030 cm
(CO); dH 0.20–0.50 (16H, m, 8!
2
2
2
3
cyclopropyl CH CH), 0.75–1.00 (4H, m, 4!cyclopropyl
2
CH), 1.05–2.25 [26H, m, 2!(CH ) , 2!CCH CH, 2!
2 4
CHCHO, 2!CCH C], 3.00–3.15 (2H, m, CHO); dC 0.0,
2
CCH C), 80.9, 83.4, (2!CH), 86.7, 87.0 (4!C), 177.8,
2
C
77.9 (2!C]O); m/z 282 (M , 5%), 225 (19), 210 (12),
1
2
2
09 (77), 135 (10), 109 (11), 97 (10), 84 (11), 83 (80), 82
0
1
.2, 0.3, 0.5, 0.9, 1.1, 1.2, 1.3 (8!cyclopropyl CH CH),
2
8.8, 18.9, 19.0, 19.1 (4!cyclopropyl CH), 24.2, 24.7, 25.3,
(
(
(
2
10), 81 (15), 79 (13), 70 (10), 69 (39), 67 (21), 57 (87), 56
15), 55 (100), 54 (16), 53 (17), 44 (18), 43 (90), 42 (22), 41
94), 40 (23). HRMS calcd for C H O 282.2195, found
28.0, 29.1, 29.9, 31.3, 32.1, 40.0, 40.1 [2!(CH
CCH CH], 44.9 (2!CHCHO), 50.1, 51.3 (2!CCH
3.5, 85.8 (2!CHO), 83.7, 88.9, 89.0, 89.1 (4!C), 177.1
)
, 2!
1
7 30 3
2
4
82.2169.
2
2
C),
8
C
5
[
.4.3. 8,8-Dicyclopropyl-2,2-dimethyl-1,7-dioxaspiro-
4.4]nonan-6-one (6e). Colourless oil; t 16.00; R 1.29
(2!C]O); m/z 276 (M , !1%), 121 (10), 95 (18), 82
(15), 81 (16), 79 (13), 67 (60), 57 (20), 55 (35), 54 (29), 44
r
f
(
hexane/EtOAc 8:2); n (film) 3048 (cyclopropyl C–H),
(100). HRMS calcd for C17
276.1731.
H
24
O
3
276.1725, found
K1
1
0
1
773 cm
(C]O); dH 0.30–0.55 (8H, m, 4!CH CH),
2
.85–1.15 (2H, 2m, 2!CH), 1.28, 1.35 (6H, 2s, 2!CH3),
.70–2.00 (4H, m, CH CH ), 2.03, 2.26 (2H, AB system,
2
2
00
00
00
0
5
.4.7. (2 R*,3a S*,7a R*)-Dispiro[cyclohexane-1,5 -
0
JZ13.9 Hz, CCH C); dC 0.6, 0.7, 1.3, 1.4 (4!CH CH),
1
2
2
0
00
tetrahydrofuran-2 -one-3 ,2 -perhydrobenzo[b]furan]
6p). Colourless oil; t 14.99; R 0.30 (hexane/EtOAc 8:2); n
(film) 1773 (C]O), 1025 cm (CO); d 1.20–2.10 (21H,
9.2, 19.3 (2!CH), 28.2, 28.9 (2!CH ), 37.6, 38.5
3
(
r
f
(
(
CH CH ), 49.2 (CCH C), 83.1, 83.8, 83.9 (3!C), 177.7
2 2 2
K1
C
H
C]O); m/z 250 (M , !1%), 191 (30), 181 (12), 177 (14),
m, 9!CH CH , CCH CH, CHCHO), 2.05, 2.21 (2H, AB
2
2
2
1
1
1
1
63 (18), 151 (20), 150 (77), 149 (11), 139 (15), 138 (13),
37 (83), 136 (12), 135 (48), 133 (11), 132 (36), 125 (11),
23 (20), 122 (16), 121 (82), 119 (12), 117 (18), 112 (48),
09 (47), 108 (14), 107 (28), 105 (12), 97 (43), 96 (24), 95
system, JZ14.0 Hz, CCH C), 3.00 (1H, td, JZ10.1, 3.4 Hz,
2
CHO); d 23.6, 23.7, 24.9, 25.8, 25.9, 28.5, 30.2, 35.5, 37.1,
0.0 (9!CH CH , CCH CH), 46.0 (CHCHO), 51.6
2 2 2
C
4
(CCH C), 84.0, 87.9 (2!C), 86.2 (CHO), 177.5 (C]O);
m/z 264 (M , 7%), 217 (16), 166 (12), 151 (12), 150 (35),
(
(
(
31), 93 (34), 91 (35), 83 (10), 82 (15), 81 (28), 80 (28), 79
38), 77 (24), 70 (19), 69 (100), 67 (42), 65 (10), 56 (10), 53
15). HRMS calcd for C H O 250.1569, found 250.1572.
2
C
1
1
1
49 (12), 147 (11), 138 (48), 137 (70), 136 (24), 135 (22),
34 (17), 132 (36), 123 (28), 122 (19), 121 (100), 119 (15),
18 (10), 117 (25), 109 (25), 108 (46), 107 (31), 105 (17), 98
1
5 22 3
00 00 0
.4.4. 5 ,5 -Diethyldispiro[adamantane-2,2 -tetrahydro-
5
0
00
00
furan-5 ,3 -tetrahydrofuran-2 -one] (6f). Colourless oil;
t 18.00; R 0.33 (hexane/EtOAc 8:2); n (film) 1770 (C]O),
(12), 96 (17), 95 (74), 94 (29), 93 (84), 91 (51), 83 (10), 82
(19), 81 (67), 80 (41), 79 (81), 77 (35), 69 (46), 68 (14), 67
(61), 66 (12), 65 (15), 55 (35), 54 (17), 53 (20). HRMS calcd
r
f
K1
1
050 cm
(CO); dH 0.80–0.95 (6H, m, 2!CH CH ),
3
2
C
1
CH CH , CCH C); d 8.6, 8.8 (2!CH ), 26.5, 26.6, 37.4,
.20–2.40 (24H, m, 2!CH CH , 4!CH, 5!CH CH,
for C16
220.1822.
H O 264.1725, (M KCO ) 220.1827, found
24 3 2
2
3
2
2
2
2
C
3

3450
F. Alonso et al. / Tetrahedron 61 (2005) 3437–3450
23. Paju, A.; Kanger, T.; Pehk, T.; Lindmaa, R.; M u¨ u¨ risepp,
Acknowledgements
A.-M.; Lopp, M. Tetrahedron: Asymmetry 2003, 14,
1565–1573.
This work was generously supported by the Direcci o´ n
General de Ense n˜ anza Superior (DGES) of the Spanish
Ministerio de Educaci o´ n, Cultura y Deporte (MECD; grant
no. BQU2001-0538) and the Generalitat Valenciana (GV;
grant no. CTIDIB/2002/318). J. M. thanks the Generalitat
Valenciana for a predoctoral grant.
24. Paju, A.; Kanger, T.; Niitsoo, O.; Pehk, T.; M u¨ u¨ risepp, A.-M.;
Lopp, M. Tetrahedron: Asymmetry 2003, 14, 2393–2399.
25. Steel, P. G. Chem. Commun. 1999, 2257–2258.
26. Di Florio, R.; Rizzacasa, M. A. J. Org. Chem. 1998, 63,
8
595–8598.
7. Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron Lett. 1997, 38,
187–2190.
2
2
2
2
8. Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron Lett. 1998, 39,
References and notes
3303–3306.
9. Lorenzo, E.; Alonso, F.; Yus, M. Tetrahedron Lett. 2000, 41,
1
. Hon, P. M.; Lee, C. M.; Shang, H. S.; Cui, Y. X.; Wong,
H. N. C.; Chang, H. M. Phytochemistry 1991, 30, 354–356.
. I n˜ arrea, P.; G o´ mez-Cambronero, J.; Nieto, M.; Crespo, M. S.
Eur. J. Pharmacol. 1984, 105, 309–315.
1661–1665.
30. Lorenzo, E.; Alonso, F.; Yus, M. Tetrahedron 2000, 56,
1745–1757.
2
31. Alonso, F.; Lorenzo, E.; Mel e´ ndez, J.; Yus, M. Tetrahedron
2003, 59, 5199–5208.
3
. Tasdemir, D.; Sitcher, O. J. Nat. Prod. 1997, 60, 874–879.
. Al-Musayeib, N. M.; Abbas, F. A.; Ahmad, M. S.; Mossa, J. S.;
El-Feraly, F. S. Phytochemistry 2000, 54, 771–775.
4
3
2. Alonso, F.; Falvello, L. R.; Fanwick, P. E.; Lorenzo, E.; Yus,
M. Synthesis 2000, 949–952.
5
. Takeda, Y.; Yanagihara, K.; Masuda, T.; Otsuka, H.; Honda,
G.; Takishi, Y.; Sezik, E.; Yesilada, E. Chem. Pharm. Bull.
3
3. Alonso, F.; Mel e´ ndez, J.; Yus, M. Helv. Chim. Acta 2002, 85,
3
262–3271.
2
000, 48, 1234–1235.
3
3
3
3
4. Review: Yus, M. Chem. Soc. Rev. 1996, 25, 155–161.
5. Ram o´ n, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225–237.
6. Yus, M. Synlett 2001, 1197–1205.
6
7
8
. Bindseil, K. U.; Henkel, T.; Zeeck, A.; Bur, D.; Niederer, D.;
S e´ quin, U. Helv. Chim. Acta 1991, 74, 1281–1286.
. Tanaka, K.; Itazaki, H.; Yoshida, T. J. Antibiot. 1992, 45,
7. Monograph: Blomberg, C. The Barbier Reaction and Related
Processes; Springer: Berlin, 1993.
5
0–55.
. Edwards, R. L.; Maitland, D. J.; Oliver, C. L.; Pacey, M. S.;
Shields, L.; Whalley, A. J. S. J. Chem. Soc., Perkin Trans. 1
3
8. Review: Alonso, F.; Yus, M. Recent Res. Dev. Org. Chem.
1
997, 1, 397–436.
1
999, 715–719.
. Goss, R. J. M.; Fuchser, J.; O’Hagan, D. Chem. Commun.
999, 2255–2256.
0. Aramaki, Y.; Chiba, K.; Tada, M. Phytochemistry 1995, 38,
419–1421.
3
9. For a preliminary communication, see: Alonso, F.; Mel e´ ndez,
J.; Yus, M. Tetrahedron Lett. 2004, 45, 1717–1720.
9
1
4
0. N a´ jera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155–181.
1. N a´ jera, C.; Yus, M. Recent Res. Dev. Org. Chem. 1997, 1,
1
1
4
1
6
7–96.
2. Yus, M.; Foubelo, F. Rev. Heteroatom Chem. 1997, 17,
3–107.
1. Midland, S. L.; Keen, N. T.; Sims, J. J.; Midland, M. M.;
Staylon, M. M.; Burton, V.; Smith, M. J.; Mazzola, E. P.;
Graham, K. J.; Clardy, J. J. Org. Chem. 1993, 58, 2940–2945.
2. Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org. Chem. 1995, 60,
4
7
4
4
3. Steward, J. J. P. J. Comp. Chem. 1991, 12, 320–341.
4. For some applications of this oxidation system, see for
instance: Berkowitz, W. F.; Perumattam, J.; Amarasekara, A.
J. Org. Chem. 1987, 52, 1119–1124.
1
1
1
1
1
1
1
1118–1119.
3. Naito, S.; Escobar, M.; Kym, P. R.; Liras, S.; Martin, S. F.
J. Org. Chem. 2002, 67, 4200–4208.
4. Calter, M. A.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002, 4,
4
5. Kauriki, B. M.; Psallidas, K.; Harris, K. D. M.; Johnston, R. L.;
Lancaster, W. R.; Staniforth, S. E.; Cooper, S. M. Chem.
Commun. 1999, 1677–1678.
2
09–212.
5. Peri, F.; Cipolla, L.; Nicotra, F. Chem. Commun. 2000,
303–2304.
2
46. Schuster, M.; G o¨ bel, H. J. Phys. D—Appl. Phys. 1995, 28,
A270–A275.
6. Cipolla, L.; Forni, E.; Jim e´ nez-Barbero, J.; Nicotra, F. Chem.
Eur. J. 2002, 8, 3976–3983.
47. Shirley, R. The Crysfire System for Automatic Powder
Indexing: User’s Manual; The Lattice: Guildford, 2002.
48. Boultif, A.; Louer, D. J. Appl. Crystallogr. 1991, 24, 987–993.
49. H o¨ ls a¨ , J.; Lahtinen, M.; Lastusaari, M.; Niittykoski, J.;
Valkonen, J. Acta Crystallogr. 2000, A56, s350.
7. Forni, E.; Cipolla, L.; Caneva, E.; la Ferla, B.; Peri, F.; Nicotra,
F. Tetrahedron Lett. 2002, 43, 1355–1357.
8. Marco-Contelles, J.; Dom ´ı nguez, L.; Anjum, S.; Ballesteros,
P.; Soriano, E.; Postel, D. Tetrahedron: Asymmetry 2003, 14,
2
865–2869.
9. For a review, see: Wong, H. N. C. Eur. J. Org. Chem. 1999,
757–1765.
5
5
5
0. Bruker AXS Topas (v. 2.1), 2000.
1
2
2
2
1. CHEM 3D Ultra, Cambridge Soft. Corp. 1985–2003.
2. Favre-Nicolin, V., F.O.X. Free Objects for Xtal Structures (v.
1
0. Ueki, T.; Doe, M.; Tanaka, R.; Morimoto, Y.; Yoshihara, K.;
Kinoshita, T. J. Heterocycl. Chem. 2001, 38, 165–172.
1. Cuzzupe, A. N.; Di Florio, R.; Rizzacasa, M. A. J. Org. Chem.
1
.6.0.2), 2000–2003.
5
3. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838.
4. See, for instance: Soler, T.; Bachki, A.; Falvello, L. R.;
Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 1998, 9,
5
2002, 67, 4392–4398.
2. Rauter, A. P.; Figueiredo, J.; Ismael, M.; Canda, T.; Font, J.;
Figueredo, M. Tetrahedron: Asymmetry 2001, 12, 1131–1146.
3
939–3943.