Straightforward synthesis of perhydrofuro[2,3-b]furans through a wacker-type reaction

Article abstract of DOI:10.1002/adsc.200800339

An efficient synthesis of substituted perhydrofuro[2,3-b]furans has been accomplished from readily accesible 3-methylidene-1,5-diols based on an intramolecular acetalisation under Wacker-type reaction conditions.

Full text of DOI:10.1002/adsc.200800339

UPDATES
DOI: 10.1002/adsc.200800339
Straightforward Synthesis of Perhydrofuro
A
Wacker-Type Reaction
Francisco Alonso,a,* Daniel Sµnchez,a Tatiana Soler,b and Miguel Yusa,*
a
Departamento de Química Orgµnica, Facultad de Ciencias, and Instituto de Síntesis Orgµnica (ISO), Universidad de
Alicante, Apdo. 99, 03080 Alicante, Spain
Fax : (+34)-9-6590-3549; e-mail: falonso@ua.esyus@ua.es
Unidad de Cristalografía de Rayos X, Servicios TØcnicos de Investigación, Facultad de Ciencias, Universidad de Alicante,
b
Apdo. 99, 03080 Alicante, Spain
Received: June 2, 2008; Revised: July 10, 2008; Published online: August 13, 2008
Abstract: An efficient synthesis of substituted
perhydrofuro[2,3-b]furans has been accomplished
G
from readily accesible 3-methylidene-1,5-diols
based on an intramolecular acetalisation under
Wacker-type reaction conditions.
Keywords: intramolecular acetalisation; palladium
catalysis; perhydrofuro
tion
A
Introduction
The perhydrofuro[2,3-b]furan unit is present in many
U
natural products with important biological activities.
Members of the clerodane family, such as lupuline A
(I), contain this fragment and show potential insect
antifeedant as well as antibacterial activity
(Figure 1).[1] The mentioned dioxabicyclic moiety is
also present in communiol D (II), isolated from the
Figure 1. Examples of perhydrofuro[2,3-b]furans.
A
[3]
fungus Podospora communis.[2] Aflatoxin B2 (III)
and asteltoxin[4] (IV) are important mycotoxins with
very potent toxicity and carcinogenecity,[5] whereas
TMC-114[6] (V) is a HIV-protease inhibitor, which has skeletons, we reported the synthesis of differently
been recently approved by the FDA for AIDS treat- substituted 3-methylidene-1,5-diols from new trime-
ment under the name Darunavir (Figure 1).
In recent years, much attention has been focused could be transformed into the corresponding
on the development of efficient methodologies for the perhydrofuro
[2,3-b]furans.[13a,b,d] This transformation
construction of perhydrofuro[2,3-b]furans because of involved three steps: hydroboration, alkaline hydro-
thylenemethane dianion synthons, which subsequently
AHCTREUNG
AHCTREUNG
their structural attractiveness and synthetic challenge. gen peroxide oxidation, and final oxidation of the hy-
Most of the methodologies to synthesise the 2,8- droxymethyl moiety in the resulting triol. The latter
dioxabicyclo
A
tramolecular cyclisation on a pre-formed tetrahydro- methane (for the hydromethylated tertiary 1,5-diols)
furan ring through lactol formation,[7] radical cyclisa- or with RuCl
2(PPh3)3 in benzene (for the hydroxyme-
A
tion,[8] haloetherification,[9] cycloaddition,[10] or intra- thylated secondary 1,5-diols) (Scheme 1). The whole
molecular carbozincation.[11] Double intramolecular process, however, cannot be considered very efficient
cyclisations from an acyclic precursor are, however, since: (a) three synthetic steps were needed with low
much less common.[12] Due to our interest in the syn- atom economy, (b) consequently, the process was
thesis of fused bicyclic[13] and spirocyclic[14] polyether time-consuming and the product yields were rather
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Straightforward Synthesis of Perhydrofuro[2,3-b]furans
A
UPDATES
Results and Discussion
The starting symmetrically-substituted methylidene-
1,5-diols 3 were prepared from commercially avail-
able 3-chloro-2-(chloromethyl)propene (1) by reac-
tion with lithium and a catalytic amount of DTBB
(4,4’-di-tert-butylbiphenyl) in the presence of different
carbonyl compounds (Scheme 2).[13d] The reagent 2-
chloromethyl-3-(2-methoxyethoxy)propene (2), de-
rived from 1, allowed the reaction with a first carbon-
yl compound through a selective chloro-lithium ex-
change at À78 to À308C, and with a second carbonyl
Scheme 1. Three-step synthesis of perhydrofuro[2,3-b]furans
from 3-methylidene-1,5-diols.
A
moderate (36–75%), (c) the reactions were performed compound at À308Cto room temperature, through
in non-green media, and (d) the rather toxic reagents an allylic carbon-oxygen bond reductive cleavage,
were used in stoichiometric amounts.
On the other hand, the palladium-catalysed intra- tuted methylidene-1,5-diols 4 (Scheme 2).[13d]
molecular Wacker-type reaction is a versatile method The palladium-catalysed cyclisation reaction under
leading to the corresponding unsymmetrically substi-
for the synthesis of oxygen-containing heterocycles.[15] Wacker-type reaction conditions was optimised using
Thus, starting from a dihydroxyalkene, interesting di- 3,7-diethyl-5-methylidenenonane-3,7-diol (3a) as the
oxabicyclic structures can be obtained, including bicy- model substrate and the results are shown in Table 1.
clic acetals.[15,16] For the cyclisation to occur, however, Initial cyclisation attempts were carried out under
the alkene must be terminal. The palladium-catalysed standard reaction conditions with the PdCl2 (10
acetalisation of alkenes has also been carried out with mol%)-CuCl2 catalytic system in different solvents
hydroxyalkenes and an alcohol (intramolecular-inter- and atmospheres. Low to modest conversions were
molecular oxypalladation),[15] or with activated sub- achieved in HOAc (Table 1, entries 1–3),[16] the pres-
strates (a,b-unsaturated carbonyl compounds) and an ence of oxygen at reflux providing the best result.
alcohol or diol (intermolecular oxypalladation).[17] In The results obtained in the most commonly used mix-
every case, the presence of a terminal alkene is man- ture of solvents for Wacker processes,[18] DMF-H2O,
datory. Geminal disubstituted alkenes are less reac- were also disappointing (Table 1, entries 4 and 5). In
tive in this reaction due to ineffective coordination of contrast, much better conversions were reached when
Pd(II) to the alkene. To the best of our knowledge, the reactions were performed in alcoholic solvents
the only examples reported so far involve methacrylo- (Table 1, entries 6–8). Up to 82% yield was obtained
yl derivatives and methanol,[15,17a] whereas the intra- in MeOH under an oxygen atmosphere at 508Cfor
molecular acetalisation of a dihydroxy-substituted 24 h (Table 1, entry 6). In an attempt to shorten the
geminal alkene has never been reported.
reaction times, we also studied the Pd(OAc)2 (10
C
present in
Wacker-type
perhydrofuro
a
3-methylidene-1,5-diol, and under whereas MeOH proved to be an inappropriate solvent
reaction conditions, leads to (Table 1, entry 12). We were very pleased, however,
[2,3-b]furans in a straightforward and ef- upon observing a 70% yield in only 4 h when the re-
ACHTREUNG
ficient manner.
action was carried out using 10 mol% PdCl2 in H2O2-
MeOH at 708C(Table 1, entry 13). This yield could
be even improved by the combined oxidating action
Scheme 2. Synthesis of the starting 3-methylidene-1,5-diols.
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Francisco Alonso et al.
UPDATES
Table 1. Optimisation of the reaction conditions for the cyclisation of 3a to 5a.
Entry
Catalyst [mol%]
Oxidant [mol%]
Solvent–atmosphere
Temperature [8C]
Time [h]
Yield [%][a]
1
2
3
4
5
6
7
8
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
CuCl2 (300)
CuCl2 (500)
CuCl2 (500)
CuCl2 (500)
CuCl2 (300)
CuCl2 (500)
CuCl2 (500)
CuCl2 (500)
H2O2 (500)
H2O2 (500)
H2O2 (500)
H2O2 (500)
HOAc/NaOAc–Ar
HOAc/NaOAc–air
HOAc–O2
DMF/H2O 7:1–air
DMF/H2O 7:1–O2
MeOH–O2
MeOH–air
EtOH–O2
HOAc–Ar
HOAc–Ar
HOAc–Ar
MeOH–Ar
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
r.t.
50
reflux
r.t.
r.t.–50
50
50
65
r.t.
80
80
50
70
70
70
70
70
70
70
24
41
10
24
24
24
24
19
17
6
15
6
4
3
8
14
28
45
10
0
82
34
70
51
45
57
trace
70
85
3
9
Pd
Pd
Pd
Pd
C
10
11
12
13
14
15
16
17
18
19
PdCl2 (10)
PdCl2 (10)
PdCl2 (1)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
H2O2 (1000)
CuCl2 (100)-H2O2 (500)
CuCl2 (10)-H2O2 (500)
CuCl2 (5)-H2O2 (500)
CuCl2 (20)-H2O2 (500)
CuCl2 (50)-H2O2 (500)
CuCl2 (100)-H2O2 (500)
8
5
8
8
20
88
96
86
[a]
Determined by GLC. The data obtained are very close to the corresponding conversion values with variations ꢀ2%.
of CuCl2 and H2O2 (Table 1, entry 14). Further opti- ently subjected to the palladium-catalysed intramolec-
misation of the amounts of catalyst and oxidants in ular cyclisation (Table 2, entries 4 and 5). The cyclisa-
the latter system (Table 1, entries 15–19) led to a final tion of meso-3d also proved to be diastereoselective,
catalytic system composed of PdCl2 (5 mol%)-CuCl2 leading to a 94:6 mixture of the perhydrofuro
A
(50 mol%)-H2O2 (500 mol%)-MeOH, with which up b]furans b-cis-5d and a-cis-5d in high yield. It is note-
to 96% yield was achieved at 708Cfor 8 h (Table 1,
worthy that under the formerly reported cyclisation
entry 18).
conditions (see Scheme 1) a ca. 1:1 mixture of the
With the optimised reaction conditions in hand, we above mentioned perhydrofuro
A
studied the palladium-catalysed intramolecular acetal- tained.[13d] On the other hand, diol dl-3d led to the ex-
isation of different methylidenic diols (Table 2). The pected perhydrofuro[2,3-b]furan trans-5d in good
C
symmetrically-substituted diols 3a–d (Table 2, en- yield.
tries 1–5) were prepared from the trimethyleneme-
We next studied the palladium-catalysed cyclisation
thane dianion synthon 1 as shown in Scheme 2. Diols of various unsymmetrically-substituted methylidenic
3a and 3b, derived from pentan-3-one and cyclohexa- diols 4, prepared from the trimethylenemethane di-
none, respectively, were cyclised in high isolated
A
yields (Table 2, entries 1 and 2). Diol 3c, derived from entries 6–8). The effectivity in the cyclisation of diol
isobutyraldehyde, was obtained as a 1:1 mixture of 4a, derived from pentan-3-one and acetone, was
diastereoisomers, its cyclisation leading to a 1:1 mix- below the average due to a loss of mass in the work-
ture of compounds b-cis-5c and trans-5c (Table 2, up procedure. In contrast, diols 4b and 4c, derived
entry 3). From these results it can be inferred that the from cyclohexanone and cyclopentanone, and cyclo-
cyclisation of meso-3c was highly diastereoselective, hexanone and tetrahydro-4H-pyran-4-one, respective-
since the corresponding product a-cis-5c, in which ly, furnished the corresponding tetracyclic products 6b
both isopropyl groups and the hydrogen atoms at the and 6c in good to high yields (Table 2, entries 7 and
ring fusion are located on opposite sides of the bicy- 8). The structure and stereochemistry of compounds 5
clic structure, was not obtained. Diols 3d derived and 6 was unequivocally assigned by comparison of
from pivalaldehyde were also obtained as a 1:1 diaste- their physical and spectroscopic data with those previ-
reomeric mixture. In this case, however, they could be ously reported by us. It is worthy of note that this
separated by column chromatography and independ- one-step Wacker-type cyclisation of diols 3 and 4 was,
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Straightforward Synthesis of Perhydrofuro[2,3-b]furans
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UPDATES
Table 2. Obtention of perhydrofuro[2,3-b]furans 5 and 6.
G
[a]
5 mol% PdCl2, 50 mol% CuCl2, 5 equiv H2O2, MeOH, 708C , 8 h.
[b]
All isolated products were
ꢁ
95% pure (GLC). Diastereomeric ratio determined by
1H NMR.
[c]
[d]
Crude yield unless otherwise stated.
GLCyield.
in every case, higher yielding than the former three- submitted to DTBB-catalysed lithiation in the pres-
step procedure.
ence of (À)-menthone. The major methylidenic diol
We also devised the possibility of synthesising obtained [commercially available (À)-menthone is
chiral non-racemic perhydrofuro[2,3-b]furans. For this 90% pure and contains isomenthone] was purified by
purpose, 3-chloro-2-(chloromethyl)propene (1) was column chromatography and assigned to the C2-sym-
AHCTREUNG
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Francisco Alonso et al.
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Scheme 3. Preparation of methylidenic diol 7 derived from (À)-menthone.
metrical diol 7 (Scheme 3). The new stereogenic cen- (d) second intramolecular oxypalladation to furnish
tres arise from the attack of the organolithium inter- the s-palladium hydride complex IX, and (e) reduc-
mediate to the less hindered carbonyl face, rendering tive elimination. Due to the presence of MeOH as a
the corresponding diaxial diol. This assignement was
unequivocally confirmed by X-ray crystallography
(Figure 2). It is worthy of note that, in contrast with
the behaviour observed for some 4-methylidene-1,7-
diols previously reported by us,[14 g] neither intramo-
lecular nor intermolecular hydrogen bonding was ob-
served for the 3-methylidene-1,5-diol 7 (Figure 3).
Methylidenic diol 7 proved to be reluctant towards
intramolecular acetalisation under the above opti-
mised reaction conditions, being cyclised in low yield
after 8 h. By using a double amount of the compo-
nents of the catalytic system, however, the reaction
reached total conversion after 24 h. The expected
product 8 was isolated in moderate yield after column
chromatography as an enantiomerically pure
perhydrofuro[2,3-b]furan (Scheme 4).
G
On the basis of related Wacker-type oxidations,[15,18]
a catalytic cycle (Scheme 5) was proposed for this
new palladium-catalysed intramolecular acetalisation
involving: (a) olefin activation by formation of the p-
complex VI, (b) intramolecular oxypalladation to give
the s-palladium intermediate VII, (c) dehydropallada-
tion leading to the p-palladium hydride complex VIII,
Figure 3. Unit cell plot of 7 in the crystal. The hydrogen
atoms, except the hydroxy group hydrogen atoms, have
been omitted for clarity.
Figure 2. Plot showing the X-ray structure and atomic num-
bering for compound 7.
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Straightforward Synthesis of Perhydrofuro[2,3-b]furans
A
UPDATES
Scheme 4. Cyclisation of methylidenic diol 7 derived from (À)-menthone.
Scheme 5. Proposed catatytic cycle for the Wacker-type intramolecular acetalisation of methylidenic diols 3, 4, and 7.
solvent in the reaction medium, intermolecular oxy- ments where the re-oxidation step was not completely
palladations leading to species of the type X-XII effective. This result is in agreement with a Pd(0)/
cannot be ruled out. In this case, intermediates XI Pd(II) mechanism operating in this reaction instead
and XII could further undergo intramolecular transa- of the alternative Pd(II)/Pd(IV) mechanism.
cetalisation reactions to afford the perhydrofuro
A
It is worthy of note that the above cyclisations
b]furans. The catalytic cycle is closed by the re-oxida- proved to be highly regioselective as products derived
tion of Pd(0) with CuCl2 and the re-oxidation of from the alternative intramolecular oxypalladations,
Cu(I) by the action of O2 and/or H2O2. It is known through intermediates VIII and XIV to XIII and XV,
that H2O2 can directly oxidise Cu(I) to Cu(II),[20] an respectively, were never observed (Scheme 6). 1,6-
additional Cu(I) oxidation by the O2 evolved from Dioxaspiro[3.4]octanes, the products that would arise
H
the palladium-catalysed H2O2 decomposition,[21] how- from the reductive elimination of XIII, were previous-
ever, cannot be disregarded. Formation of small ly obtained, however, by intramolecular iodoetherifi-
amounts of Pd(0) has been observed in some experi- cation of diols 3.[14a] On the other hand, products de-
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Francisco Alonso et al.
UPDATES
teraction involving the two tert-butyl groups. This in-
teraction is, however, minimised in transition state
XIX, which through intermediate XXI would lead to
b-cis-5d as the major product.
Conclusions
We have reported, for the first time, the palladium-
catalysed intramolecular acetalisation of a dihydroxy-
substituted geminal alkene. The cyclisation is carried
out under optimised Wacker-type conditions, involv-
ing catalytic palladium(II), substoichiometric cop-
Scheme 6.
AHCTREUNG
rived from XV are not formed, very probably, because of
the dehydropalladation of VII to VIII, involving the perhydrofuro
ACHTREUNG
À
OC H bond, prevails over that of VII to XIV.
A high stereoselectivity was achieved in the cyclisa-
We also tried to rationalise the high stereoselectiv- tion reaction of meso compounds. Moreover, an enan-
ity observed in the cyclisation of meso-3c and meso- tiomerically pure perhydrofuro[2,3-b]furan has also
G
3d, which is exemplified for the tert-butyl derivative been successfully synthesized in a straightforward
meso-3d in Scheme 7. Starting from the two plausible manner from (À)-menthone. The methodology de-
p-palladium hydride complexes XVI and XVII, re- scribed herein represents a notable improvement with
sulting from a first cyclisation, the corresponding and respect to that previously reported by us since (a) the
hypothetical transition states XVIII and XIX have whole transformation is carried out in one pot (one
been proposed for the second cyclisation. Transition vs. three synthetic steps) with higher atom economy,
state XVIII shows a clear and unfavourable steric in- (b) the process is faster, (c) the product yields are
higher, (d) the reaction is performed in a greener
medium, and (e) catalytic amounts of less toxic re-
agents are used.
Experimental Section
General Remarks
Melting points were obtained with a Reichert Thermovar
apparatus. Optical rotations were measured with a Perkin–
Elmer 341 polarimeter with a thermally jacketted 5 cm cell
at approximately 208C. Concentrations (c) are given in g/
100 mL and [a] values are given in units of 10À1 deg cm2 gÀ1.
NMR spectra were recorded on a Bruker Avance 300 and
1
Bruker Avance 400 (300 and 400 MHz for H NMR, and 75
and 100 MHz for 13CNMR, respectively). Mass spectra (EI)
were obtained at 70 eV on an Agilent 5973 spectrometer.
HR-MS 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 instrument equipped with a flame
ionisation detector and a 30 m capillary column (0.32 mm di-
ameter, 0.25 mm film thickness), using nitrogen (2 mLminÀ1)
as carrier gas, Tinjector =2758C, Tcolumn =608C(3 min) and 60–
2708C(15 8CminÀ1). Flash column chromatography was per-
formed using silica gel 60 of 40–60 microns. PdCl2 (Merck),
CuCl2 (Aldrich), H2O2 (Acros), and MeOH (Panreac) were
commercially available.
The starting methylidenic diols 3, 4, and 7 were prepared
following previously reported procedures.[13d] Compounds 3
and 4 were characterised by comparison of their physical
Scheme 7.
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Straightforward Synthesis of Perhydrofuro[2,3-b]furans
A
UPDATES
and spectroscopic data with those previously reported.[13d]
Data for new compound 7 are given below.
ter, based on three w-scan runs (starting w=À348) at the
values of ø=08, 1208, 2408 with the detector at 2q=À328.
For each of these runs, 606 frames were collected at 0.38 in-
tervals. An additional run at ø=08 of 100 frames was col-
lected to improve redundancy. The diffraction frames were
integrated using the SAINT[22] programme and the integrat-
ed intensities were corrected for Lorentz polarisation effects
with SADABS.[23]
A
thylcyclohexyl]methyl}prop-2-enyl)-2-isopropyl-5-methylcy-
clohexan-1-ol (7): Colourless solid; tr =18.68; Rf =0.49
(hexane-EtOAc 96:4); mp 1058C(hexane); [ a]2D0: +12.0 (c
À
1.0, CH2Cl2)À;1 IR (KBr): n=3541 (O H), 3066, 1625, 891
(HC=C ) cm ; 1H NMR (300 MHz, CDCl3): d=0.76–1.02,
1.31–1.77 (2m, 34H, 6”CH3, 6”C H, 4”CH), 1.91, 3.12
X-ray data for 7:[24] C24H44O2, M=364.59; orthorhombic,
a=8.5673(10) Š, b=10.5340(12) Š, c=25.875(3) Š; V=
2
(2d, J=14.0 Hz, 4H, 2”CH2C=CH2), 2.14–2.23 (m, 2H, 2”
CH), 2.57 (s, 2H, 2”OH), 4.80 (s, 2H, H2C=C); 13CNMR
(75 MHz, CDCl3): d=18.1, 22.6, 23.8, 25.5, 28.0, 51.6 (6”
CH3, 6”CH), 20.8, 35.0, 46.6, 47.2 (8”CH2), 74.7 (2”CO),
117.3 (H2C=C), 144.8 (C=CH2); MS (EI): m/z (%)=364
(M+, <1), 346 (M+ÀH2O, 2), 192 (10), 177 (26), 155 (63),
149 (25), 138 (10), 137 (100), 136 (17), 112 (10), 95 (30), 83
(11), 81 (55), 69 (44), 55 (31); HR-MS: m/z=346.3221,
calcd. for C24H44O2: 364.3341 [M+ÀH2O]: 346.3236.
2335.2(5) Š3; space group P212121; Z=4; 1cald
=
1.037 MgmÀ3; l=0.71073 Š; m=0.063 mmÀ1; F
(000)=816;
A
T=23Æ18C. The structure was solved by direct methods[25]
and refined to all 2371 unique F2 by full matrix least
o
squares (SHELX97).[26] All the hydrogen atoms were placed
at idealised positions and refined as rigid atoms. Final
wR2=0.1324 for all data and 243 parameters; R1 =0.0502
for 1797 Fo > 4s(Fo).
Palladium-Catalysed Cyclisation of the Methylidenic
Diols 3,4,and 7; General Procedure
Acknowledgements
A solution of PdCl2 (8.9 mg, 0.05 mmol), CuCl2 (67.2 mg),
MeOH (10 mL), and the corresponding diol (1 mmol) was
prepared in a screw top tube, followed by the addition of a
35% H2O2 solution (0.43 mL). The top was airtight on the
reaction tube which was heated at 708Cfor 8 h. Then,
hexane (20 mL) and saturated NaCl solution (10 mL) were
added to the resulting mixture. The aqueous phase was ex-
tracted with hexane (6”20 mL) and the organic phase was
dried with anhydrous Na2SO4 followed by filtration through
celite. The filtrate was evaporated (15 Torr), giving the cor-
This work was generously supported by the Spanish Ministe-
rio de Educación y Ciencia(MEC; grant no. CTQ2004-01261
and CTQ2007-65218; Consolider Ingenio 2010-CSD2007-
00006) and the Generalitat Valenciana (GV; grant no.
GRUPOS03/135). D. S. thanks the Vicerrectorado de Investi-
gación, Desarrollo e Innovación of the University of Alicante
for a predoctoral grant.
responding perhydrofuro[2,3-b]furan as an oil, that in the
U
case of compound 8 was purified by column chromatogra-
phy (silica gel, hexane/ether).
References
The perhydrofuro[2,3-b]furans 5 and 6 were characterised
N
[1] a) F. Camps, J. Coll, Phytochemistry 1993, 32, 1361–
1370; b) H. Chen, R. X. Tan, Z. L. Liu, Y. Zhang, J.
Nat. Prod. 1996, 59, 668–670.
by comparison of their physical and spectroscopic data with
those previously reported.[13d] Data for the new compound 8
are given below.
[2] a) Y. Che, J. B. Gloer, J. A. Scott, D. Malloch, Tetrahe-
dron Lett. 2004, 45, 6891–6894; b) M. Enomoto, T. Na-
kahata, S. Kuwahara, Tetrahedron 2006, 62, 1102–1109.
[3] For reviews, see: a) R. E. Minto, C. A. Townsed, Chem.
Rev. 1997, 97, 2537–2555; b) C. A. Townsed, R. E.
Minto, in: Comprehensive Natural Products Chemistry,
Vol. 1, (Eds.: D. Barton, K. Nakanishi, D. Meth-Cohn,
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Dispiro
cis-tetrahydrofurano
ACHTREUNG
AHCTREUNG
pyl-4-methylcyclohexane}] (8): Colourless oil; tr =18.51; Rf =
0.61 (hexane-ether, 96:4); [a]2D0: À12.5 (c 0.7, CH2Cl2); IR
(neat): n=1383, 1364 cmÀ1 (CH, i-Pr); H NMR (400 MHz,
1
CDCl3): d=0.73–0.96 (6d, J=6.8 Hz, 18H, 6”CH3), 0.97–
1.04, 1.39–1.51, 1.56–1.82, 1.87–1.93, 2.06–2.13 [5 m, 21H, 8”
CH2, 5”CH), 2.19–2.25 [dd, J=13.2, 10.4 Hz, 1H, CH],
2.77–2.87 (m, 1H, CHCHCO), 5.52 (d, J=5.7 Hz, 1H,
OCHO); 13C NMR (100 MHz, CDCl3): d=17.9, 18.7, 22.4,
24.1, 26.1, 26.5 (6”CH3), 22.1, 22.5, 35.0, 35.3, 41.5, 42.9 (2”
CH2CH-i-Pr, 2 ” CH2CH2CH-i-Pr, 2”CCH2CHCH3), 27.9,
29.0, 42.8, 47.5, 50.4 [6”CHCH3, CHCHO, 2”CH-i-Pr],
47.6, 51.2 (OCCH2CHCH2CO), 87.8, 90.5 [2”CH2CO],
109.4 (OCHO); MS (EI): m/z (%)=362 (M+, 18), 344 (17),
277 (48), 189 (12), 176 (16), 175 (100), 174 (24), 151 (13),
149 (18), 137 (15), 135 (12), 109 (15), 95 (30), 93 (10), 83
(12), 81 (25), 69 (39), 67 (13), 55 (27); HR-MS: m/z=
362.3186, calcd. for C24H42O2: 362.3185.
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X-Ray Crystallography
Compound 7 was recrystallised from diethyl ether. Data col-
lection was performed on a Bruker Smart CCD diffractome-
Adv. Synth. Catal. 2008, 350, 2118 – 2126
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2125

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graphic data for this paper (compound 7). These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Copies can also be obtained, free of
charge, on application to CCDC, 12 Union Road, Cam-
bridge, CB2 1EZ, UK (fax: +44–1223–336033; email:
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2126
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Adv. Synth. Catal. 2008, 350, 2118 – 2126