Ultrasound-promoted formation of isopentenyl alcohol dianion: Straightforward synthesis of perhydrofuro[2,3- b ]furans

Article abstract of DOI:10.1055/s-0030-1258168

Ultrasound has been found to accelerate the formation of isopentenyl alcohol dianion by metalation with butyllithium in diethyl ether- tetrahydrofuran. The reaction of this dianion with carbonyl compounds followed by intramolecular acetalization under Wacker-type conditions provides a direct route for the synthesis of 2-substituted perhydrofuro[2,3-b]furans. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258168

PAPER
3013
Ultrasound-Promoted Formation of Isopentenyl Alcohol Dianion:
Straightforward Synthesis of Perhydrofuro[2,3-b]furans
Synthesis of
P
r
e
rhydrof
a
uro[2,3-
b
]f
n
urans cisco Alonso,* Mamen Rodríguez-Fernández, Daniel Sánchez, Miguel Yus*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax +34(965)903549; E-mail: falonso@ua.es; E-mail: yus@ua.es
Received 4 May 2010
Dedicated to the memory of Professor José Manuel Concellón
species. Some representative examples of this family of
natural products are lupulin C4a (I) and scutecolumnin C
(II)5a (Figure 2). In some cases, a perhydrofuro[2,3-b]fu-
ran-2-one moiety is also present in the clerodanes, arising
Abstract: Ultrasound has been found to accelerate the formation of
isopentenyl alcohol dianion by metalation with butyllithium in di-
ethyl ether–tetrahydrofuran. The reaction of this dianion with car-
bonyl compounds followed by intramolecular acetalization under
Wacker-type conditions provides a direct route for the synthesis of from the oxidation of the hemiacetal functionality, i.e.
III.6 These compounds exhibit manifold biological activ-
2-substituted perhydrofuro[2,3-b]furans.
ity, especially as antifeedants of insects.7 Model com-
Key words: metalation, ultrasound, polyanions, Wacker-type reac-
tion, cyclization, perhydrofuro[2,3-b]furans
pounds IV and V are synthetic analogues that were found
to display insect antifeedant activity in laboratory
bioassays8 (Figure 2). In addition, compound V (R = Me)
is a key intermediate in the synthesis of artificial ana-
logues of mycalamide A.9 The reported synthetic routes to
compounds of the type IV and V are, however, rather
long.8–10 Alternative approaches to obtain 2-substituted
perhydrofuro[2,3-b]furans in a more straightforward
manner are, therefore, welcome.
2-Methylprop-2-en-1-ol (methallyl alcohol, 1) and 3-meth-
ylbut-3-en-1-ol (isopentenyl alcohol, 2) are inexpensive
and commercially available building blocks, which,
through a double direct metalation reaction, can be readily
transformed into synthetically useful molecules
(Figure 1). The formation of dianions 4 and 5 from 1 and
2 was first described in the 1970s using, respectively,
Schlosser’s base in hexane or butyllithium/TMEDA in
hexane.1 A modification of the latter procedure was later
introduced by Trost et al. by using a diethyl ether–tetrahy-
drofuran solvent mixture and optimized for the prepara-
tion of allylsilanes derived from 1 and 2.2 In more recent
literature, the direct trimetalation of 2,4-dimethylpenta-
1,4-dien-3-ol (3) was conducted with sec-butyllithium/
TMEDA in diethyl ether–cyclohexane, with the derived
organolithium intermediate 6 being trapped with various
electrophiles.3
O
O
O
O
H
H
H
H
H
H
O
H
O
H
O
H
O
O
O
OAc
OAc
AcO
AcO
OH
lupulin C (I)
scutecolumnin C (II)
III
H
H
OH
OH
R
R
O
OH
O
O
O
O
H
H
1
2
5
3
IV
V
OLi
R = alkyl, cycloalkyl, aryl
R = alkyl, cycloalkyl, aryl
OLi
Li
OLi
Li
Li
Li
Figure 2
4
6
Due to our continued interest in the synthesis of fused
bicyclic11 and spirocyclic12 polyether skeletons, we re-
cently published a highly efficient synthesis of 2,5-substi-
tuted perhydrofuro[2,3-b]furans. The strategy was based
on the arene-catalyzed lithiation of allylic chlorinated
substrates and subsequent reaction with carbonyl com-
pounds, followed by intramolecular acetalization of the
resulting 3-methylene-1,5-diols under Wacker-type reac-
tion conditions.13 The latter step represents the first
Figure 1
Perhydrofuro[2,3-b]furans substituted at the 2-position
can be found as substructures in clerodane diterpenes,
which are especially abundant in Ajuga4 and Scutellaria5
SYNTHESIS 2010, No. 17, pp 3013–3020
Advanced online publication: 12.07.2010
DOI: 10.1055/s-0030-1258168; Art ID: Z11410SS
x
x.
x
x
.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

3014
F. Alonso et al.
PAPER
palladium-catalyzed intramolecular acetalization of a di-
hydroxy-substituted geminal alkene (Scheme 1).
i) NaH, THF, r.t., 1 h
ii) TBDMSCl, r.t., 1 h
OH
OTBDMS
80%
i) Li, DTBB (5%)
R12CO,THF
R1
R1
R2
R2
CeCl3•7H2O, NaClO
OTBDMS
Cl
X
Cl
Et
ii) H2O or
CH2Cl2/H2O, r.t., 3 h
OH
OH
iii) R22CO and H2O
75% conversion
OTBDMS
X = Cl, OCH2CH2OMe
R1 = R2 or R1 ≠ R2
i) Li, DTBB cat., THF, –78 °C, 3 h
ii) Et2CO, –78 °C to r.t., overnight
H
Et
PdCl2 (5 mol%)
CuCl2 (50 mol%)
R2
R2
R1
R1
OH
40%
H2O2, MeOH
70 °C, 8 h
O
O
H
Et
Et
Scheme 1 Synthesis of 2,5-substituted perhydrofuro[2,3-b]furans
through arene-catalyzed lithiation and Wacker-type reactions
OH
TBAF, THF, r.t., 24 h
OH
100% conversion
We wish to present herein a new and direct route for the
synthesis of 2-substituted perhydrofuro[2,3-b]furans in-
volving the generation of isopentenyl alcohol dianion un-
der ultrasound irradiation and intramolecular cyclization
under Wacker-type reaction conditions. A protocol for the
direct oxidation of the perhydrofuro[2,3-b]furan moiety to
the corresponding lactone has been also studied.
Scheme 2 Preliminary synthesis of a 3-methylene-1,5-diol precur-
sor of a 2-substituted perhydrofuro[2,3-b]furan
i) 10 M n-BuLi, TMEDA
Et2O–THF, r.t., 48 h
OH
Me3Si
Me3Si
OSiMe3
ii) TMSCl, –78 °C to r.t.,
15 min
1
2
7
52%
Initial attempts to obtain the precursor diols following a
similar strategy to the aforementioned route was rather
long and, therefore, not very efficient (Scheme 2). The
whole process involved protection of isopentenyl alcohol,
allylic chlorination,14 arene-catalyzed lithiation15 in the
presence of a carbonyl compound, and deprotection. In-
stead, we decided to use isopentenyl alcohol (2) as the di-
rect source of dianion 5 and study its reactivity with
carbonyl compounds. The reaction of methallyl alcohol
dianion 4 with ketones was described by Carlson,1b al-
though the yields of the corresponding diols were modest
(15–40%). The reactivity of trianion 6 was not tested with
carbonyl compounds3 whereas that of dianion 5 was main-
ly reported with chlorosilanes2 and allyl1a and alkyl ha-
lides.16 To the best of our knowledge, there is only one
example in the literature of the reaction of dianion 5 with
carbonyl compounds (two aldehydes), as the key step in
the synthesis of vitamin A and methyl (2E,4E)-3,7,11-tri-
methyldodeca-2,4-dienoate.17 Therefore, it would be of
interest to study the generation and reactivity of dianion 5
with carbonyl compounds in more detail.
i) 10 M n-BuLi, TMEDA
Et2O–THF, r.t., 48 h
OSiMe3
OH
ii) TMSCl, –78 °C to r.t.,
15 min
8
52%
Scheme 3 Synthesis of allylsilanes 7 and 8 through conventional
metalation conditions
i) 10 M n-BuLi, TMEDA
Et2O–THF, ))), 6 h
OH
Me3Si
Me3Si
OSiMe3
ii) TMSCl, –78 °C to r.t.,
15 min
1
2
7
53%
i) 10 M n-BuLi, TMEDA
Et2O–THF, ))), 6 h
OSiMe3
OH
ii) TMSCl, –78 °C to r.t.,
15 min
8
51%
Scheme 4 Synthesis of allylsilanes 7 and 8 through ultrasound-
promoted dianion formation
We first tested the reaction conditions as reported by Trost
et al. for the synthesis of allylsilanes 7 and 8 from 1 and 2;
they were both obtained in 52% isolated yield
(Scheme 3).2 The only objection to this methodology is
the long reaction time required for the generation of the
corresponding dianions 4 and 5, respectively. We ob-
served, however, that the reaction times were notably
shortened under ultrasound irradiation18 whilst maintain-
ing the product yields (Scheme 4).
(Table 1). Within the different experiments performed
with 10 M butyllithium in diethyl ether–tetrahydrofuran
and TMEDA at room temperature (entries 1–5), the best
results were obtained using 5.2 equivalents of TMEDA
and 3.0 equivalents of pentan-3-one (entry 4). The slow
addition of the electrophile at –78 °C (entry 5), however,
minimized the formation of byproducts when carbonyl
compounds other than pentan-3-one were used, especial-
ly, aldehydes. Different reaction conditions reported in
the literature, some of which for polyanion formation and
reaction with some other electrophiles, gave poorer yields
and/or complex mixtures. Such is the case for butyllithi-
Based on this methodology, a variety of reaction condi-
tions were screened in order to optimize both the dianion
formation of 2 and its reactivity toward carbonyl com-
pounds, using pentan-3-one as the model electrophile
Synthesis 2010, No. 17, 3013–3020 © Thieme Stuttgart · New York

PAPER
Synthesis of Perhydrofuro[2,3-b]furans
3015
Table 1 Optimization of the Double Metalation of 2 and Reaction with Pentan-3-onea
Et
Et
i) base, conditions
ii) Et2CO
OH
OH
OH
2
9a
Entry
1
Base (equiv)
Solvent, conditions
Et2O–THF (3:2), MW
Et2O–THF (3:2), MW
Et2O–THF (3:2), MW
Et2O–THF (3:2), MW
Et2O–THF (3:2), MW
Et2O
Additive (equiv)
Equiv of Et2CO Yieldb (%)
10 M BuLi (3.0)
10 M BuLi (3.0)
10 M BuLi (3.0)
10 M BuLi (3.0)
10 M BuLi (3.0)
2 M BuLi (2.0)
10 M BuLi (3.0)
2.5 M BuLi (2.0)
1.4 M s-BuLi (4.7)
1.7 M t-BuLi (3.0)
Li(CH2)4OLid (3.5)
TMEDA (2.6)
TMEDA (2.6)
TMEDA (5.2)
TMEDA (5.2)
TMEDA (5.2)
TMEDA (2.6)
–
1.0
2.0
2.0
3.0
3.0c
0.5
1.0
1.0
3.0
3.0
1.0
35
44
48
58
58
2
3
4
5
616
719
817
93
complex mixture
toluene, MW
24
hexane
TMEDA (2.0)
TMEDA (5.3)
TMEDA (5.2)
–
37
Et2O–cyclohexane (3:2)
Et2O–THF (3:2), MW
THF, MW
complex mixture
complex mixture
23
10
1120
a Dianion formation at r.t. for 6 h (12 h in entry 8, 4 h in entry 9), followed by reaction with pentan-3-one at –78 °C to r.t. overnight.
b Isolated yield after column chromatography.
c Slow addition of the ketone (–78 °C for 3 h), overnight at –78 °C to r.t.
d Generated from THF and Li-DTBB.20
um in diethyl ether–TMEDA (entry 6),16 toluene (entry Diols 9 were subjected to intramolecular acetalization un-
7),19 or hexane–TMEDA (entry 8);17 sec-butyllithium in der Wacker-type reaction conditions as previously de-
diethyl ether–cyclohexane–TMEDA (entry 9),3 tert-bu- scribed by us (Scheme 6, Table 2).13 The diols derived
tyllithium in diethyl ether–tetrahydrofuran–TMEDA (en- from pentan-3-one 9a and cyclohexanone 9b cyclized
try 10) or the dianion resulting from the reductive nicely to afford the corresponding perhydrofuro[2,3-
cleavage of tetrahydrofuran with lithium 4,4¢-di-tert-bu- b]furans 10a and 10b in high yields (entries 1 and 2). In
tylbiphenyl (Li-DTBB) (entry 11).20
contrast, diol 8c derived from benzophenone gave the
product 10c in modest yield (entry 3). Acetalization of di-
ols derived from aldehydes 9d–f proceeded stereoselec-
tively in modest-to-moderate isolated yields (entries 4–6).
A maximum 93:7 diastereromeric ratio was reached in the
acetalization of the diol derived from cyclohexanecarbal-
dehyde 9e (entry 5). The major (2R*,3aR*,6aS*) relative
configuration observed is in agreement with that previ-
ously reported by us for 2,5-substituted perhydrofuro[2,3-
b]furans13 and was confirmed by NOE experiments con-
ducted on both diastereomers of compound 10f
(Figure 3). A small NOE was observed for H2 and H3a in
both diastereomers, whereas NOE between H2 and H5
was manifested only in the major diastereomer. PM321 ge-
ometry optimization revealed the closer location of H2
and H5 in (2R*,3aS*,6aR*)-10f compared with that in
(2S*,3aS*,6aR*)-10f (Figure 3). It is noteworthy that
quantitative conversion of the starting methylene diols
was recorded in all cases. An important loss of mass, how-
ever, was observed for compounds 10c,d during their pu-
rification by column chromatography, probably due to
partial decomposition. The general longer reaction times
required for the formation of 2-substituted or 2,2-disubsti-
tuted compounds 10 (24 h) in comparison with the 2,5-
The optimized reaction conditions were extended to other
carbonyl compounds, including three different ketones
and aldehydes bearing alkyl, cycloalkyl, and aryl substit-
uents (Scheme 5, Table 2). Within the ketones, pentan-3-
one gave the best result (entry 1), with the methylene diols
9b and 9c derived from cyclohexanone and benzophe-
none, respectively, being obtained in modest yields (en-
tries 2 and 3). A similar performance was observed for
valeraldehyde, cyclohexanecarbaldehyde, and benzalde-
hyde, which gave 9d–f in 32–66% yield (entries 3–6).
Notwithstanding the low yields, the fact that the reaction
could be carried on a 10-mmol scale allowed the methyl-
ene diols 9 to be obtained in substantial and practical
amounts.
i) 10 M n-BuLi, TMEDA
R2
Et2O–THF, ))), 6 h
OH
OH
R1
ii) R1R2CO, –78 °C to r.t.,
12 h
OH
2
9
R1R2CO = Et2CO, (CH2)5CO, Ph2CO, Me(CH2)3CHO, c-C6H11CHO, PhCHO
Scheme 5 Reaction of isopentenyl alcohol dianion with various car-
bonyl compounds
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3016
F. Alonso et al.
PAPER
disubstituted or 2,2,5,5-tetrasubstituted counterparts (8 hydrofuro[2,3-b]furan 10e described by de Groot et al.8b
h)13 could be attributed somewhat to the gem-dialkyl ef- involved the noncommercial 4,4-diethoxybutanenitrile
fect.22
and 2-cyclohexyloxirane starting materials in a nine-step
sequence. In contrast, only two steps, from commercially
available isopentenyl alcohol and cyclohexanecarbalde-
hyde, were involved in our methodology, which, in addi-
tion, resulted in a higher product stereoselectivity
(Scheme 7).
H
H
PdCl2 (5 mol%)
CuCl2 (50 mol%)
R2
R1
OH
R2
R1
H2O2, MeOH
70 °C, 24 h
O
O
OH
10
9
Finally, we studied the possibility to access the perhydro-
furo[2,3-b]furan-2-one moiety by direct oxidation of the
perhydrofuro[2,3-b]furan core of 10a. Among the differ-
ent conditions tested, the oxidation with catalytic rutheni-
um(IV) oxide and stoichiometric sodium periodate in the
dichloromethane–water–acetonitrile solvent system gave
the best outcome of lactone 11a (Scheme 8).23
Scheme 6 Cyclization of methylene diols 9 to perhydrofuro[2,3-
b]furans 10 under Wacker-type conditions
In spite of the fact that the overall yields for compounds
10 are not as optimum as desired, the methodology pre-
sented herein is the most direct route reported so far to this
type of compounds. As an example, the synthesis of per-
Table 2 Synthesis of Methylene-1,5-diols 9 and Perhydrofuro[2,3-b]furans 10
Entry
Diol 9
Yielda (%)
58
Productb 10
Yielda (%)
94c
H
OH
OH
1
O
O
OH
H
9a
9b
10a
10b
H
2
3
42
31
89c
O
O
OH
H
H
H
33
OH
O
O
OH
9c
10c
H
H
H
OH
4
5
6
31
30
35
48
32
66
O
O
O
O
OH
H
9d
(2R*,3aR*,6aS*)-10d
(2S*,3aR*,6aS*)-10d
89:11
H
H
OH
O
O
O
O
H
H
OH
(2R*,3aS*,6aR*)-10e
(2S*,3aS*,6aR*)-10e
9e
9f
93:7
H
H
OH
O
O
O
O
H
H
OH
(2R*,3aS*,6aR*)-10f
(2S*,3aS*,6aR*)-10f
85:15
a All isolated products were ≥95% pure (GLC). Isolated yield after column chromatography (silica gel, hexane–EtOAc) unless otherwise stated.
b Diastereomeric ratio determined by 1H NMR.
c Reaction crude yield.
Synthesis 2010, No. 17, 3013–3020 © Thieme Stuttgart · New York

PAPER
Synthesis of Perhydrofuro[2,3-b]furans
3017
Figure 3 NOE experiments and optimized geometry models for the diastereomeric perhydrofuro[2,3-b]furans 10f; numbers on the arrows
refer to interatomic distances in Å
CDCl3 as solvent and TMS as internal standard. Mass spectra (EI)
O
H
were obtained at 70 eV on an Agilent 5973 spectrometer. HRMS
analyses were carried out on a Finnigan MAT95S spectrometer.
The purity of volatile compounds and the chromatographic analyses
(GLC) were determined with a Hewlett Packard HP-6890 instru-
ment equipped with a flame ionization detector and a 30 m capillary
column (0.32 mm diameter, 0.25 mm film thickness), using N2 (2
mL/min) as carrier gas, Tinjector = 275 °C, Tcolumn = 60 °C (3 min) and
60–270 °C (15 °C/min). Sonication was carried out on a JP Selecta
Ultrasons apparatus (6 L, 150 W, 40 kHz). Flash column chroma-
tography was performed using silica gel 60 (40–60 m). Methallyl al-
cohol (Aldrich), isopentenyl alcohol (Aldrich), 10 M BuLi
(Aldrich), TMEDA (Alfa Aesar), anhyd Et2O (Fluka, 99.8%, H2O
£0.005%), the carbonyl compounds (Aldrich, Alfa Aesar), PdCl2
(Merck), CuCl2 (Aldrich), 35% H2O2 (Acros), MeOH (Panreac),
RuO2·xH2O (Aldrich), NaIO4 (Riedel de Häen), CH2Cl2 (Panreac),
and MeCN (Panreac) are commercially available. THF was dried in
a Sharlab PS-400-3MD solvent purification system using an alumi-
na column.
9 steps
ref. 8b
EtO
CN
+
O
O
OEt
H
10e
67% de
H
CHO
2 steps
OH
+
this paper
O
O
H
4
10e
86% de
Scheme 7 Comparative synthesis of perhydrofuro[2,3-b]furan 10e
according to the literature approach8b and that described herein
H
H
H
RuO2 (cat.), NaIO4
CH2Cl2–H2O–MeCN
Synthesis of Allylsilanes 7 and 8 and Methylene-1,5-diols 9;
General Procedure
O
O
O
O
O
Methallyl alcohol (1, 0.84 mL, 10 mmol) or 3-methylbut-3-enol (2,
1 mL, 10 mmol) was added dropwise to a soln of 10 M n-BuLi (3
mL, 30 mmol) in anhyd Et2O (12 mL) and anhyd TMEDA (8 mL)
at 0 °C under an inert atmosphere. Then, anhyd THF (8 mL) was
added to the mixture and it was stirred at 0 °C for a few min. The
flask content was sonicated for 6 h with formation of a deep red pre-
cipitate attributed to the corresponding dianions. Next, the corre-
sponding electrophile (30 mmol) in anhyd Et2O (5 mL) was slowly
added (for allylsilanes slow addition was not required) at –78 °C
over 3 h and the mixture was stirred for an additional 12 h (15 min
for allylsilanes) and the temperature was allowed to reach r.t. The
reaction was quenched with H2O (10 mL), acidified with 3 M HCl,
and extracted with Et2O (3 × 40 mL). The resulting combined or-
ganic phases were sequentially washed with sat. CuSO4 soln (2 × 10
mL, in order to quench the TMEDA) and H2O (2 × 10 mL). The new
organic phase was dried (anhyd MgSO4) and the solvent was evap-
orated (20 mbar) to give a crude product that was purified by col-
umn chromatography (silica gel, hexane–EtOAc). The allylsilanes
7 and 8 were characterized by comparison of their physical and
spectroscopic data with those reported in the literature.2 New com-
pounds 9 are as given below.
H
11a
10a
60%
Scheme 8 Oxidation of perhydrofuro[2,3-b]furan 10a to lactone
11a
In conclusion, we have developed a new synthesis of 2-
substituted perhydrofuro[2,3-b]furans based on the ultra-
sound-promoted generation of the dianion of isopentenyl
alcohol and reaction with carbonyl compounds, followed
by palladium-catalyzed intramolecular acetalization un-
der Wacker-type reaction conditions. The methodology
has been applied both to ketones and aldehydes, with the
perhydrofuro[2,3-b]furans arising from the latter being
obtained stereoselectively. Although the overall yields are
modest, this approach represents the most direct route to
this kind of compounds. Moreover, their transformation
into the corresponding lactones can be easily accom-
plished by ruthenium-catalyzed oxidation. Further studies
regarding the reactivity of these compounds are under-
way.
5-Ethyl-3-methyleneheptane-1,5-diol (9a)
Colorless oil; GLC: tR = 10.28 min; Rf = 0.33 (hexane–EtOAc, 1:1).
IR (film): 3362 (OH), 3073, 1638 cm–1 (CH=C).
1H NMR (300 MHz, CDCl3): d = 0.87 (t, J = 7.6 Hz, 6 H, 2 CH3),
1.50 (q, J = 7.6 Hz, 4 H, 2 CH2CH3), 2.23 (br s, 2 H, 2 OH), 2.43 (t,
J = 5.9 Hz, 2 H, CH2CH2OH), 3.75 (t, J = 5.9 Hz, 2 H,
CH2CH2OH), 4.91, 5.00 (2 s, 2 H, H2C=C).
Melting points were obtained with a Reichert Thermovar apparatus.
IR analysis was performed with a FT-IR Nicolet Impact 400D spec-
trophotometer. NMR spectra were recorded on 300 and 400 spec-
trometers [300 and 400 MHz (1H) and 75 and 100 MHz (13C)] using
Synthesis 2010, No. 17, 3013–3020 © Thieme Stuttgart · New York

3018
F. Alonso et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 8.0 (2 CH3), 30.9 (2 CH2CH3),
40.4 (CH2CH2OH), 44.2 (CH2COH), 61.2 (CH2OH), 75.0 (COH),
116.0 (H2C=C), 143.9 (C=CH2).
1-Cyclohexyl-3-methylenepentane-1,5-diol (9e)
Colorless oil; GLC: tR = 12.96 min; Rf = 0.33 (hexane–EtOAc,
1:1).
MS (EI): m/z (%) = 154 [M+ – H2O] (<1), 87 (100), 69 (26), 57 (60).
IR (KBr): 3354 (OH), 3075, 1644 cm–1 (CH2=C).
HRMS: m/z [M+] calcd for C10H20O2: 172.1463; m/z [M+ – H2O]
calcd for C10H18O: 154.1358; found: 154.1376.
1H NMR (300 MHz, CDCl3): d = 0.85–1.48, 1.62–1.91 [2 m, 11 H,
(CH2)5CH], 1.92–2.15, 2.26–2.40 (2 m, 6 H, 2 OH, CH2CCH2), 3.51
(ddd, J = 10.3, 5.6, 2.9 Hz, 1 H, CHOH), 3.75 (t, J = 6.2 Hz, 2 H,
CH2OH), 5.00 (s, 2 H, H2C=C).
13C NMR (75 MHz, CDCl3): d = 26.1, 26.2, 26.5, 28.2, 29.0
[(CH2)5], 38.9 (CH2CH2OH), 40.8 (CH2CHOH), 43.6 (CHCOH),
60.6 (CH2OH), 73.5 (CHOH), 114.7 (H2C=C), 144.0 (C=CH2).
1-(4-Hydroxy-2-methylenebutyl)cyclohexanol (9b)
White solid; mp 55 °C; GLC: tR = 11.90 min; Rf = 0.44 (hexane–
EtOAc, 1:1).
IR (KBr): 3415 (OH), 3076, 1638 cm–1 (CH=C).
1H NMR (300 MHz, CDCl3): d = 1.20–1.70 [m, 10 H, (CH2)5], 2.24
(s, 2 H, CCH2COH), 2.42 (t, J = 6.1 Hz, 2 H, CH2CH2OH), 2.51 (br
s, 2 H, 2 OH), 3.75 (t, J = 6.1 Hz, 2 H, CH2CH2OH), 4.91, 5.00 (2
s, 2 H, H2C=C).
13C NMR (75 MHz, CDCl3): d = 22.2 (2 CH2CH2COH), 25.6
(CH2CH2CH2COH), 37.8 (2 CH2COH), 40.5 (CH2CH2OH), 47.7
(CH2COH), 61.08 (CH2OH), 71.5 (COH), 115.9 (H2C=C), 143.4
(C=CH2).
MS (EI): m/z (%) = 180 [M+ – H2O] (<1%), 143 (11), 113 (44), 95
(100), 83 (26), 69 (15), 68 (27), 67 (28), 56 (11), 55 (30).
HRMS: m/z [M+] calcd for C12H22O2: 198.1620; m/z [M+ – H2O]
calcd for C12H20O: 180.1514; found: 180.1531.
3-Methylene-1-phenylpentane-1,5-diol (9f)
Colorless oil; GLC: tR = 13.07 min; Rf = 0.33 (hexane–EtOAc,
1:1).
MS (EI): m/z (%) = 166 [M+ – H2O] (2), 100 (10), 99 (100), 81 (59),
IR (KBr): 3354 (OH), 3064, 3029, 1644, 1494 cm–1 (CH=C).
79 (11), 55 (18).
1H NMR (300 MHz, CDCl3): d = 2.25–2.57 (m, 4 H, CH2CCH2),
3.78 (t, J = 5.9 Hz, 2 H, CH2OH), 4.75–4.90 (m, 1 H, CHOH), 5.04,
5.05 (2 s, 2 H, H2C=C), 7.20–7.45 (m, 5 H, 5 ArH).
HRMS: m/z [M+] calcd for C11H20O2: 184.1463; m/z [M+ – H2O]
calcd for C11H18O: 166.1358; found: 166.1352.
13C NMR (75 MHz, CDCl3): d = 39.0 (CH2CH2OH), 46.1
(CH2CHOH), 60.6 (CH2OH), 72.5 (CHOH), 115.4 (H2C=C), 125.7,
127.6, 128.5 (5 ArH), 143.1 (ArC), 144.0 (C=CH2).
MS (EI): m/z (%) = 192 [M+] (<1), 174 [M+ – H2O] (4), 129 (10),
107 (100), 105 (14), 79 (45), 77 (30).
HRMS: m/z [M+] calcd for C12H16O2: 192.1150; m/z [M+ – H2O]
calcd for C12H14O: 174.1045; found: 174.101.
3-Methylene-1,1-diphenylpentane-1,5-diol (9c)
Colorless oil; GLC: tR = 16.70 min; Rf = 0.61 (hexane–EtOAc,
1:1).
IR (film): 3382 (OH), 3059, 3025, 1644, 1493 cm–1 (CH=C).
1H NMR (400 MHz, CDCl3): d = 1.94 (t, J = 6.1 Hz, 2 H,
CH2CH2OH), 3.13 (s, 2 H, CH2COH), 3.78 (t, J = 6.1 Hz, 2 H,
CH2OH), 4.82, 4.96 (2 s, 2 H, H2C=C), 7.15–7.55 (m, 10 H, 10
ArH).
13C NMR (100 MHz, CDCl3): d = 39.8 (CH2CH2OH), 47.5
(CH2COH), 60.7 (CH2OH), 76.8 (COH), 117.8 (H2C=C), 125.9,
126.8, 128.0 (10 ArCH), 142.4 (2 ArC), 146.8 (C=CH2).
MS (EI): m/z (%) = 250 [M+ – H2O,] (29), 232 (10), 220 (18), 217
(16), 206 (14), 205 (54), 204 (22), 203 (23), 202 (20), 184 (12), 183
(84), 182 (24), 178 (11), 165 (13), 128 (10), 105 (100), 91 (10), 77
(49), 51 (10).
Palladium-Catalyzed Cyclization of the Methylene-1,5-diols 9;
General Procedure
A soln of PdCl2 (8.9 mg, 0.05 mmol), CuCl2 (67.2 mg), MeOH (10
mL), and the corresponding methylene-1,5-diol 9 (1 mmol) was
prepared in a screw-top tube, followed by the addition of 35% H2O2
soln (0.86 mL, 10 mmol). The top was airtight on the reaction tube,
which was heated at 70 °C for 24 h. The solvent was evaporated to
dryness, followed by the addition of EtOAc (20 mL) and filtration
through Celite. The filtrate was washed with brine (2 × 5 mL), the
organic phase was dried (anhyd MgSO4), and the solvent evaporat-
ed under vacuum (20 mbar). Compounds 10a and 10b did not re-
quire any further purification, while compounds 10c–f were
purified by column chromatography (silica gel, hexane–EtOAc).
HRMS: m/z [M+] calcd for C18H20O2: 268.1463; m/z [M+ – H2O]
calcd for C18H18O: 250.1358; found: 250.1348.
3-Methylenenonane-1,5-diol (9d)
Colorless oil; GLC: tR = 10.65 min; Rf = 0.33 (hexane–EtOAc,
1:1).
(3aR*,6aS*)-2,2-Diethylhexahydrofuro[2,3-b]furan (10a)
Colorless oil; GLC: tR = 9.28 min; Rf = 0.48 (hexane–EtOAc, 8:2).
IR (film): 1024 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): d = 0.85, 0.90 (2 t, J = 7.5 Hz, 6 H, 2
CH3), 1.35–1.75, 1.88–2.07 (2 m, 8 H, 2 CH2CH3, CH2CHCH2),
2.85–3.00 (m, 1 H, CH2CHCH2), 3.84–3.95 (m, 2 H, CH2O), 5.68
(d, J = 5.1 Hz, 1 H, OCHO).
IR (film): 3345 (OH), 3075, 1644 cm–1 (CH=C).
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 7.0 Hz, 3 H, CH3),
1.20–1.55 [m, 6 H, (CH2)3], 1.96 (br s, 2 H, 2 OH), 2.10 (dd, J = 9.8,
6.9 Hz, 1 H, CHAHBCHOH), 2.25–2.40 (m, 3 H, CH2CH2OH,
CHAHBCHOH), 3.65–3.85 (m, 3 H, CHOH, CH2OH), 4.99 (s, 2 H,
H2C=C).
13C NMR (100 MHz, CDCl3): d = 14.1 (CH3), 22.7, 27.9
(CH2CH2CH3), 37.0 (CH2CH2CHOH), 38.9 (CH2CH2OH), 44.1
(CCH2CHOH), 60.64 (CH2OH), 69.6 (CHOH), 114.8 (H2C=C),
143.6 (C=CH2).
MS (EI): m/z (%) = 172 [M+] (<1), 154 [M+ – H2O] (2), 117 (25),
87 (65), 85 (12), 69 (100), 68 (68), 67 (50), 57 (19), 56 (32), 55 (11),
53 (11).
13C NMR (100 MHz, CDCl3): d = 8.4, 8.7 (2 CH3), 30.5, 31.2 (2
CH2CH3), 32.8 (CH2CH2CO), 39.2 (CHCH2COC), 43.1
(CH2CHCH2), 65.8 (CH2O), 88.0 (CO), 109.1 (OCHO).
MS (EI): m/z (%) = 170 [M+] (<1), 141 (100), 95 (20), 57 (55), 55
(15).
HRMS: m/z [M+] calcd for C10H18O2: 170.1307; m/z (M+ – C2H5)
calcd for C8H13O2: 141.0910; found: 141.0899.
HRMS: m/z [M+] calcd for C10H20O2: 172.1463; m/z [M+ – H2O]
calcd for C10H18O: 154.1358; found: 154.1351.
Synthesis 2010, No. 17, 3013–3020 © Thieme Stuttgart · New York

PAPER
Synthesis of Perhydrofuro[2,3-b]furans
3019
(3a¢R*,6a¢S*)-Tetrahydro-3¢H-spiro[cyclohexane-1,2¢-furo[2,3-
1H NMR (400 MHz, CDCl3): d = 0.85–1.10, 1.10–1.47, 1.50–1.85,
1.90–2.20 [4 m, 15 H, (CH2)5, CH2CHCH2, c-Hex CH2CHCH2],
2.75–2.95 (m, 1 H, CH2CHCH2), 3.61–3.97 (m, 3 H, CH2O, CHO),
5.70 (d, J = 5.0 Hz, 1 H, OCHO).
b]furan] (10b)
Colorless oil; GLC: tR = 11.02 min; Rf = 0.40 (hexane–EtOAc,
8:2).
IR (KBr): 1020 cm–1 (C–O).
13C NMR (100 MHz, CDCl3): d = 25.8, 26.0, 26.4, 28.8, 30.0
[(CH2)5], 32.8 (CH2CH2O), 36.5 (CH2CHCH2), 68.2 (CH2O), 84.2
(CHO), 108.7 (OCHO).
1H NMR (300 MHz, CDCl3): d = 1.20–1.80, 1.85–2.14 (2 m, 14 H,
7 CH2), 2.85–3.01 (m, 1 H, CH2CHCH2), 3.80–4.00 (m, 2 H,
CH2O), 5.68 (d, J = 5.2 Hz, 1 H, OCHO).
MS (EI): m/z (%) = 196 [M+] (<1), 152 (10), 113 (100), 69 (37), 55
(13).
13C NMR (75 MHz, CDCl3): d = 23.3, 23.7, 25.4 [2 CH2CH2C,
CH2(CH2)2C], 32.5 (CH2CH2O), 36.9, 38.1 (2 CH2CH2C), 41.2
(CCH2CH), 42.4 (CH2CHCH2), 65.6 (CH2O), 84.3 (CO), 108.4
(OCHO).
MS (EI): m/z (%) = 182 [M+] (20), 140 (19), 139 (100), 126 (30),
121 (11), 84 (10), 82 (25), 81 (13), 67 (11), 55 (23).
HRMS: m/z [M+] calcd for C12H20O2: 196.1463; found: 196.1432.
Selected data for the minor diastereomer (2S*,3aS*,6aR*)-10e:
GLC: tR = 12.45 min.
1H NMR (400 MHz, CDCl3): d = 5.62 (d, J = 5.5 Hz, 1 H, OCHO).
MS (EI): m/z (%) = 196 [M+] (<1), 113 (100), 69 (37), 55 (13).
HRMS: m/z [M+] calcd for C11H18O2: 182.1307; found: 182.1332.
(2R*,3aS*,6aR*)-2-Phenylhexahydrofuro[2,3-b]furan (10f)8b
Colorless oil; GLC: tR = 12.91 min; Rf = 0.35 (hexane–EtOAc,
8:2).
(3aR*,6aS*)-2,2-Diphenylhexahydrofuro[2,3-b]furan (10c)
White solid; mp 95 °C; GLC: tR = 16.46 min; Rf = 0.46 (hexane–
EtOAc, 8:2).
IR (KBr): 3053, 3021, 1595, 1490 (CH=C), 1011 cm–1 (C–O).
IR (KBr): 3062, 3030, 1603, 1494 (CH=C), 1016 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): d = 1.80–1.90, 1.98–2.10, 2.14–2.30
(3 m, 4 H, CH2CHCH2), 2.97–3.09 (m, 1 H, CH2CHCH2), 3.91–
4.10 (m, 2 H, CH2O), 5.12 (dd, J = 5.7, 5.0 Hz, 1 H, CHO), 5.93 (d,
J = 4.9 Hz, 1 H, OCHO), 7.24–7.46 (m, 5 H, 5 ArH).
13C NMR (100 MHz, CDCl3): d = 32.5 (CH2CH2O), 41.6
(CH2CHO), 43.0 (CH2CHCH2), 68.4 (CH2O), 84.8 (CHO), 109.4
(OCHO), 125.7, 127.5, 128.4 (5 ArCH), 141.5 (ArC).
MS (EI): m/z (%) = 190 [M+] (10), 145 (10), 143 (10), 129 (38), 128
(15), 117 (13), 115 (17), 107 (20), 105 (21), 104 (21), 91 (22), 84
(100), 83 (19), 78 (10), 77 (22), 70 (27), 69 (14), 56 (15), 55 (20).
HRMS: m/z [M+] calcd for C12H14O2: 190.0994; found: 190.0989.
Selected data for the minor diastereomer (2S*,3aS*,6aR*)-10f:
GLC: tR = 12.45 min.
1H NMR (300 MHz, CDCl3): d = 1.65 (dd, J = 6.2, 5.0 Hz, 1 H,
CHAHBCH2O), 1.84–1.98 (m, 1 H, CHAHBCH2O), 2.15 (dd, J = 8.5,
6.3 Hz, 1 H, CHAHBC), 2.75–2.90 (m, 1 H, CH2CHCH2), 3.03 (dd,
J = 8.7, 6.3 Hz, 1 H, CHAHBC), 3.75–3.85 (m, 1 H, CHAHBO), 3.93
(dd, J = 6.8, 5.7 Hz, 1 H, CHAHBO), 5.79 (d, J = 5.3 Hz, 1 H,
OCHO), 7.10–7.60 (m, 10 H, 10 ArH).
13C NMR (75 MHz, CDCl3): d = 31.9 (CH2CH2O), 42.7 (CH2C),
43.1 (CH2CHCH2), 66.5 (CH2O), 88.6 (CO), 108.7 (OCHO), 125.4,
125.6, 126.8, 128.0, 128.2 (10 ArCH), 145.3, 145.9 (2 ArC).
MS (EI): m/z (%) = 266 [M+] (10), 190 (10), 189 (62), 184 (14), 183
(100), 178 (12), 165 (18), 115 (10), 105 (48), 91 (12), 84 (13), 77
(19).
HRMS: m/z [M+] calcd for C18H18O2: 266.1307; found: 266.1271.
1H NMR (400 MHz, CDCl3): d = 5.81 (d, J = 5.5 Hz, 1 H, OCHO).
MS (EI): m/z (%) = 190 [M+] (6), 129 (31), 128 (16), 117 (11), 115
(16), 107 (21), 105 (21), 104 (22), 91 (21), 84 (100), 83 (19), 77
(22), 70 (22), 69 (14), 56 (15), 55 (20).
(2R*,3aR*,6aS*)-2-Butylhexahydrofuro[2,3-b]furan (10d)
Colorless oil; GLC: tR = 10.70 min; Rf = 0.50 (hexane–EtOAc, 8:2).
IR (KBr): 1015 cm–1 (C–O).
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 6.9 Hz, 3 H, CH3),
1.20–1.50 [m, 6 H, (CH2)3], 1.50–1.78, 1.78–1.90, 2.04–2.20 (3 m,
4 H, CH2CHCH2), 2.75–2.95 (m, 1 H, CH2CHCH2), 3.79–3.99 (m,
2 H, CH2O), 4.00–4.15 (m, 1 H, CHO), 5.71 (d, J = 5.1 Hz, 1 H,
OCHO).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.7, 28.3
(CH3CH2CH2), 32.7, 35.3, 38.8 (CH2CHCH2, CH3CH2CH2CH2),
42.6 (CH2CHCH2), 68.2 (CH2O), 79.7 (CHO), 108.9 (OCHO).
MS (EI): m/z (%) = 170 [M+] (<1), 113 (100), 84 (12), 69 (48), 67
(10), 55 (16).
HRMS: m/z [M+] calcd for C10H18O2: 170.1307; found: 170.1332.
Selected data for the minor diastereomer (2S*,3aR*,6aS*)-10d:
GLC: tR = 10.60 min.
(3aR*,6aS*)-5,5-Diethyltetrahydrofuro[2,3-b]furan-2(6aH)-
one
Following a variant of a literature procedure for the oxidation of a
tetrahydrofuran ring:23 Compound 10a (170 mg, 1 mmol) was slow-
ly added to a soln of RuO2·xH2O (27 mg) and NaIO4 (856 mg, 4
mmol) in CH2Cl2–H2O–MeCN (2:2:1, 5 mL). The mixture was
stirred at r.t. for 6 h, followed by the addition of H2O (10 mL) and
extraction with CH2Cl2 (3 × 10 mL). The combined organic extracts
were dried (anhyd MgSO4), concentrated under vacuum (20 mbar),
and purified by column chromatography (silica gel, hexane–EtOAc,
1:1) to give pure lactone 11a as a colorless oil; GLC: tR = 11.52
min; Rf = 0.51 (hexane–EtOAc, 1:1).
IR (film): 1778 (C=O), 1116 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): d = 5.63 (d, J = 5.3 Hz, 1 H, OCHO).
MS (EI): m/z (%) = 170 [M+] (<1), 113 (100), 84 (15), 69 (47), 67
1H NMR (400 MHz, CDCl3): d = 0.89 (2 t, 6 H, J = 7.5, Hz, 2 CH3),
1.50–1.75 (m, 5 H, 2 CH2CH3, CHAHBCO), 2.19 (dd, J = 13.2, 9.9
Hz, 1 H, CHAHBCO), 2.49 (dd, J = 17.9, 1.3 Hz, 1 H, CHAHBCO2),
2.79 (dd, J = 17.9, 8.5 Hz, 1 H, CHAHBCO2), 3.07–3.18 (m, 1 H,
CH2CHCH2), 6.01 (d, J = 5.1 Hz, 1 H, OCHO).
13C NMR (100 MHz, CDCl3): d = 8.3, 8.5 (2 CH3), 31.1, 32.2 (2
CH2CH3), 36.5 (CH2CO2), 39.5 (CH2CO), 40.1 (CH2CHCH2), 92.2
(CO), 109.1 (OCHO), 174.4 (CO2).
(11), 55 (17).
(2R*,3aS*,6aR*)-2-Cyclohexylhexahydrofuro[2,3-b]furan
(10e)8b
Colorless oil; GLC: tR = 12.57 min; Rf = 0.55 (hexane–EtOAc, 8:2).
IR (KBr): 1018, 1097 cm–1 (C–O).
Synthesis 2010, No. 17, 3013–3020 © Thieme Stuttgart · New York

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F. Alonso et al.
PAPER
MS (EI): m/z (%) = 184 [M+] (<1), 155 [M+ – C2H5] (100), 137 (18),
127 (14), 112 (10), 111 (11), 109 (13), 97 (10), 96 (15), 81 (12), 70
(10), 69 (17), 57 (41), 55 (16).
HRMS: m/z [M+] calcd for C10H16O3: 184.1099; m/z [M+ – C2H5]
calcd C8H11O3: 155.0703; found: 155.0737.
(9) Fukui, H.; Tsuchiya, Y.; Fujita, K.; Nakagawa, T.; Koshino,
H.; Nakata, T. Bioorg. Med. Chem. Lett. 1997, 7, 2081.
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Yoshikoshi, A. J. Chem. Soc., Chem. Commun. 1990, 418.
(b) Kido, F.; Sinha, S. C.; Abiko, T.; Watanabe, M.;
Yoshikoshi, A. Tetrahedron 1990, 46, 4887.
(11) (a) Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron Lett. 1997,
38, 2187. (b) Alonso, F.; Lorenzo, E.; Yus, M. Tetrahedron
Lett. 1998, 39, 3303. (c) Lorenzo, E.; Alonso, F.; Yus, M.
Tetrahedron Lett. 2000, 41, 1661. (d) Lorenzo, E.; Alonso,
F.; Yus, M. Tetrahedron 2000, 56, 1745. (e) Alonso, F.;
Lorenzo, E.; Meléndez, J.; Yus, M. Tetrahedron 2003, 59,
5199. (f) Alonso, F.; Meléndez, J.; Yus, M. Russ. Chem.
Bull. 2003, 52, 2628. (g) Alonso, F.; Meléndez, J.; Yus, M.
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Acknowledgment
This work was generously supported by the Spanish Ministerio de
Educación y Ciencia (MEC; grant no. CTQ2007-65218 and Conso-
lider Ingenio 2010-CSD2007-00006) and the Generalitat Valencia-
na (grant no. PROMETEO/2009/039). D. S. and M. R.-F. thank the
Vicerrectorado de Investigación, Desarrollo e Innovación of the
University of Alicante for predoctoral and postdoctoral grants, re-
spectively.
(12) (a) Alonso, F.; Falvello, L. R.; Fanwick, P. E.; Lorenzo, E.;
Yus, M. Synthesis 2000, 949. (b) Alonso, F.; Meléndez, J.;
Yus, M. Helv. Chim. Acta 2002, 85, 3262. (c) Alonso, F.;
Meléndez, J.; Yus, M. Tetrahedron Lett. 2004, 45, 1717.
(d) Alonso, F.; Dacunha, B.; Meléndez, J.; Yus, M.
Tetrahedron 2005, 61, 3437. (e) Dacunha, B.; Alonso, F.;
Meléndez, J.; Yus, M. Acta Crystallogr., Sect. A 2005, 61,
C157. (f) Meléndez, J.; Alonso, F.; Yus, M. Tetrahedron
Lett. 2006, 47, 1187. (g) Alonso, F.; Meléndez, J.; Soler, T.;
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Foubelo, F.; Yus, M. Curr. Chem. Biol. 2007, 1, 317.
(i) Alonso, F.; Meléndez, J.; Yus, M. Synlett 2008, 1627.
(13) Alonso, F.; Sánchez, D.; Yus, M. Adv. Synth. Catal. 2008,
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(14) Moreno-Dorado, F.; Guerra, F. M.; Manzano, F. L.; Aladro,
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Jansen, B. J. M.; de Groot, A. Tetrahedron 1999, 55, 11051.
Synthesis 2010, No. 17, 3013–3020 © Thieme Stuttgart · New York