Synthesis of perhydrofuro[2,3-b]furans from isopentenyl alcohol through carbonyl-ene and wacker-type reactions

Article abstract of DOI:10.1002/ejoc.201100961

A range of 2-substituted perhydrofuro[2,3-b]furans have been synthesized in a stereoselective manner through a sequence involving the Lewis-acid catalyzed carbonyl-ene reaction of a protected isopentenyl alcohol with a variety of enophiles, deprotection of the corresponding monoprotected diols, and palladium-catalyzed intramolecular acetalization under Wacker-type reaction conditions. A new synthetic approach toward the synthesis of perhydrofuro[2,3-b]furans is described. The strategy is based on the carbonyl-ene reaction for a protected isopentenyl alcohol with several activated enophiles followed by deprotection and palladium-catalyzed intramolecular acetalization. Copyright

Full text of DOI:10.1002/ejoc.201100961

FULL PAPER
DOI: 10.1002/ejoc.201100961
Synthesis of Perhydrofuro[2,3-b]furans from Isopentenyl Alcohol through
Carbonyl-Ene and Wacker-Type Reactions
Francisco Alonso,*[a] Mamen Rodríguez-Fernández,[a] Daniel Sánchez,[a] and Miguel Yus[a]
Dedicated to Professor K. C. Nicolaou on the occasion of his 65th birthday
Keywords: Natural products / Synthetic methods / Oxygen heterocycles / Ene reaction / Wacker reaction /
Perhydrofurofurans
A range of 2-substituted perhydrofuro[2,3-b]furans have
been synthesized in a stereoselective manner through a se-
quence involving the Lewis-acid catalyzed carbonyl-ene re-
action of a protected isopentenyl alcohol with a variety of
enophiles, deprotection of the corresponding monoprotected
diols, and palladium-catalyzed intramolecular acetalization
under Wacker-type reaction conditions.
Introduction
Perhydrofuro[2,3-b]furans possess an interesting bicyclic
acetal structure which is present in many natural prod-
ucts.[1] In particular, those with substituents at the 2-posi-
tion can be found as substructures in neoclerodane diter-
penes which are especially abundant in Ajuga[2] and Scutel-
laria[3] species. Lupulin C (I),[2a] scutecolumnin C (II),[3a]
and areptin A (III)[2c] are some representative examples of
this family of natural products (Figure 1) which exhibit no-
table insect antifeedant activity.[4] Compounds IV and V
are synthetic analogs with the latter displaying the above-
mentioned activity in laboratory bioassays.[5] The reported
synthetic routes for these types of compounds are, however,
rather long.[4–6] Therefore, the design of alternative ap-
proaches to attain 2-substituted perhydrofuro[2,3-b]furans
in a straightforward manner would be welcome.
Figure 1. Natural and synthetic 2-substituted perhydrofuro[2,3-b]-
furans.
Our continuous interest in the synthesis of fused bicy-
clic[7] and spirocyclic[8] polyether skeletons led us to dis-
cover a new and highly efficient synthesis of 2,5-substituted
perhydrofuro[2,3-b]furans. The strategy consisted of the ar-
ene-catalyzed lithiation of allylic chlorinated substrates and
subsequent reaction with carbonyl compounds, followed by
an intramolecular acetalization of the resulting 3-methyl-
idene-1,5-diols under Wacker-type reaction conditions.[9]
More recently, we developed a new synthesis of 2-substi-
tuted perhydrofuro[2,3-b]furans based on the ultrasound-
promoted generation of the dianion of isopentenyl alcohol
and reaction with carbonyl compounds, followed by the
aforementioned intramolecular acetalization.[10] This meth-
odology was applied to both ketones and aldehydes with
the perhydrofuro[2,3-b]furans obtained stereoselectively
from the latter (Scheme 1). Although the overall yields were
modest, this approach represents hitherto, to the best of
our knowledge, the most direct route to these compounds.
In addition, their transformation into the corresponding
lactones was easily accomplished by ruthenium-catalyzed
oxidation.
Notwithstanding the advantages of this methodology, all
the perhydrofurofurans synthesized bore hydrocarbon sub-
stituents because of the incompatibility of the dianion of
isopentenyl alcohol with many functional groups. We
sought to synthesize more functionalized methylidenic 1,5-
diols, and we identified the carbonyl-ene reaction as a po-
[a] Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax: +34-965903549
E-mail: falonso@ua.es
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FULL PAPER
knowledge, there is only one example reported of its reac-
tion with isopentenyl alcohol which, in the presence of
Me2AlCl, led to a mixture of three products.[17] We ob-
served that BF3·Et2O at 0 °C gave the expected product in
moderate conversion, although substantial amounts of by-
products were present irrespective of the reaction con-
ditions (Table 1, Entries 1–3). Catalytic amounts of
Cu(OTf)2 and TiCl4 or stoichiometric amounts of SnCl4
and AlCl3 exerted very little effect, albeit approximately a
25% conversion was observed with the latter (Table 1, En-
tries 4–7). We were delighted with the performance of the
organoaluminium Lewis acid Me2AlCl which provided high
conversion to and good isolated yield of the desired product
(Table 1, Entry 8).
Scheme 1. Straightforward synthesis of perhydrofuro[2,3-b]furans
through the isopentenyl alcohol dianion and Wacker-type reaction.
tential solution. An alternative to the carbonyl addition of
allylmetals, this is an atom-efficient carbon–carbon bond-
forming reaction, in which an alkene bearing an allylic hy-
drogen (the ene) is treated with a carbonyl compound (the
enophile), accompanied by migration of the double bond
and a 1,5-hydrogen shift.[11] The intermolecular version of
this reaction is entropically disfavored in comparison to the
intramolecular counterpart, and, hence, the carbonyl group
needs to be highly activated. Lewis acid promoters, such as
aluminium halides, and catalysts, such as SnCl4, BF3·OEt2,
Sc(OTf)3, or Yb(OTf)3, enable the ene reactions to proceed
at room or low temperature. Most of the research concern-
ing the intermolecular processes is focused on non-func-
tionalized hydrocarbon-based enes.[12] A few reports deal
with protected methallyl alcohol as the ene component,[13]
whereas the carbonyl-ene reaction with isopentenyl alcohol
has seldom been studied.[14] We wish to present herein a
new and straightforward route towards the synthesis of
functionalized 2-substituted perhydrofuro[2,3-b]furans in-
volving the carbonyl-ene reaction of protected isopentenyl
alcohol with activated enophiles, followed by deprotection
and an oxidation–acetalization reaction under Wacker-
type[15] conditions.
Table 1. Carbonyl-ene reaction of 1 with paraformaldehyde (2a).
Entry Lewis acid
[mol-%]
1/2a
[mmol] [°C]
T
t
[h]
Product[a]
[%]
1
2
3
4
5
6
7
8
BF3·Et2O [119]
1:1
1:1
1:1
1:10
1:1
2:1
1:1
1:1
–10
–10
0
r.t.
–70 to –30
–78
0
3.5
5
3
24
48
16
24
16
1 [56][b]
BF3·Et2O [119]
BF3·Et2O [119]
Cu(OTf)2 [10]
TiCl4 [10]
SnCl4 [100]
AlCl3 [150]
1 [9], 3a [13][b]
3a [46][b]
1 [95]
1 [94], 3a [6]
1 [79], 3a [2]
1 [73], 3a [26]
3a [91] (72)
Me2AlCl [220]
0 to r.t.
[a] Determined from the GLC (gas–liquid chromatography) peak
area. The isolated yield is in parentheses. [b] Substantial amounts
of byproducts were obtained.
Next, we studied the behavior of 2-oxoesters as the en-
ophiles, starting with ethyl glyoxylate (2b). In this case, both
TiCl4 and Me2AlCl gave low conversions to 3b (Table 2,
Entries 1 and 2). The AgSbF6/rac-BINAP-PdCl2 combina-
tion [BINAP = 2,2Ј-bis(diphenylphosphino)-1,1Ј-binaphth-
yl], which proved to be effective in the asymmetric version
of the glyoxylate- and phenylglyoxal-ene reaction with hy-
Results and Discussion
Initial attempts for a direct reaction between isopentenol drocarbon enes,[18] furnished the expected product in mod-
and either paraformaldehyde or ethyl glyoxylate, in the erate conversion independent of the temperature and reac-
presence of variable amounts of different Lewis acids, led tion time (Table 2, Entries 3 and 4). In contrast, SnCl4 gave
to complex mixtures and/or starting material. A maximum more satisfactory results, and catalytic amounts of this
20% conversion to the desired homoallylic diol was re- Lewis acid led to moderate conversions and byproduct for-
corded for the reaction with ethyl glyoxylate promoted by mation (Table 2, Entries 5 and 6). However, the outcome of
SnCl4 (1 equiv.) at –78 °C after 72 h. Therefore, we decided the reaction was especially good at low temperature with
it was more convenient to carry out all the ene reactions stoichiometric amounts of the Lewis acid and a prolonged
with isopentenol protected as the tert-butyldimethylsilyl reaction time (Table 2, Entries 7 and 8).
(TBDMS) ether 1. Unfortunately, we were unable to find a
A stoichiometric amount of SnCl4 was also chosen to
Lewis acid that could be generally applied in the reactions promote the carbonyl-ene reaction of 1 with ethyl pyruvate
with a range of enophiles. Consequently, selection of the (2c) (Table 3, Entry 3). It is noteworthy that, under the reac-
Lewis acid and optimization of the reaction conditions were tion conditions, partial deprotection towards the corre-
mandatory for every enophile.
sponding diol 4c was observed. Rather than being a prob-
Paraformaldehyde has been one of the most studied en- lem, this fact was somewhat advantageous as compounds 3
ophiles with hydrocarbon enes, generally giving modest were later subjected to protodesilylation. Upon scaling the
yields of the homoallylic alcohols.[16] To the best of our reaction to Ͼ1 mmol, carbon–carbon double-bond isomer-
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Synthesis of Perhydrofuro[2,3-b]furans from Isopentenyl Alcohol
Table 2. Carbonyl-ene reaction of 1 with ethyl glyoxylate (2b).
Table 4. Carbonyl-ene reaction of 1 with ethyl 3,3,3-trifluoropyruv-
ate (2d).
Entry Lewis acid
[mol-%]
1/2b
[mmol] [°C]
T
t
Product[a]
[h] [%]
Entry Lewis acid
[mol-%]
1/2d
[mmol] [°C]
T
t
Product[a]
[h] [%]
1
2
3
TiCl4 [10]
1:1
1:1
1:2.2
–70 to –30
0 to r.t.
–78
24 1 [89], 3b [11]
27 1 [65], 3b [35]
3.5 1 [42], 3b [58]
Me2AlCl [220]
AgSbF6 [11],
BINAP-PdCl2 [5]
AgSbF6 [11],
BINAP-PdCl2 [5]
SnCl4 [10]
SnCl4 [10]
SnCl4 [50]
SnCl4 [100]
1
2
SnCl4 [100]
AgSbF6 [11],
1:1
1:2.2
0
–78
24 1 [35], 4d [40][b]
4
1 [Ͼ99]
BINAP-PdCl2 [5]
AgSbF6 [11],
BINAP-PdCl2 [5]
AgSbF6 [11],
4
1:1
r.t.
31 1 [60], 3b [40]
3
4
1:2.2
1:1
–78
–30
67 1 [65], 3d [35]
44 1 [27], 3d [42]
5
6
7
8
1:1
1:1
2:1
1:1
r.t.
0
–78
–78
32 3b [60][b]
48 3b [71][b] (10)
16 1 [90], 3b [10]
72 3b [96] (66)
BINAP-PdCl2 [5]
EtAlCl2 [220]
Me2AlCl [220]
5
6
1:1
1:1
0 to r.t. 20 1 [54], 3d [23][c]
0 to r.t. 27 1 [44], 3d [50]
(12)[d], 4d [6] (6)[b]
[a] Determined from the GLC peak area. The isolated yield is in
parentheses. [b] Substantial amounts of a byproduct were obtained.
[a] Determined from the GLC peak area. The isolated yield is in
parentheses. [b] Deprotected 3d. [c] 22% of the double-bond isom-
erization product was obtained. [d] 6% of the double-bond isomer-
ization occurred giving rise to approximately a 3:1 mixture ization product was obtained.
of 3c and (E)-ethyl 6-[(tert-butyldimethylsilyl)oxy]-2-hy-
droxy-2,4-dimethylhex-4-enoate.
with the aluminium Lewis acids as well as with SnCl4 at
0 °C or room temperature (Table 5, Entries 1–5). Very mod-
est conversion and isolated yield were only achieved with
SnCl4 at low temperature, though it was fortunate that the
reaction was scalable to 10 mmol (Table 5, Entry 6).
Table 3. Carbonyl-ene reaction of 1 with ethyl pyruvate (2c).
Table 5. Carbonyl-ene reaction of 1 with diethyl oxomalonate (2e).
Entry Lewis acid
[mol-%]
1/2c
T
t
Product[a]
[h] [%]
[mmol] [°C]
1
2
3
Me2AlCl [220]
EtAlCl2 [220]
SnCl4 [100]
1:1
1:1
1:1
0 to r.t. 22 1 [93], 3c [7]
0 to r.t. 24 3c [24], 4c [10][b]
–78
21 3c [64] (40),
4c [15] (14)[b]
Entry Lewis acid
[mol-%]
1/2e
T
t
[h]
Product[a]
[%]
[mmol] [°C]
[a] Determined from the GLC peak area. The isolated yield is in
parentheses. [b] Deprotected 3c.
1
2
3
4
5
6
Me2AlCl [220]
EtAlCl2 [220]
SnCl4 [10]
SnCl4 [10]
SnCl4 [100]
SnCl4 [100]
1:1
1:1
1:1
1:1
1:1
1:1
0 to r.t.
0 to r.t.
0
r.t.
0 or r.t.
–78
24
22
24
24
72
44
1 [33], 3e [12]
3e [4]
3e [6][b]
Despite being more activated than ethyl pyruvate (2c),
ethyl 3,3,3-trifluoropyruvate (2d) was a rather problematic
enophile. For instance, a stoichiometric amount of SnCl4
afforded a near equimolar ratio of 1 and deprotected prod-
uct 4d together with multiple byproducts (Table 4, Entry 1).
The AgSbF6/rac-BINAP-PdCl2 combination was shown to
be somewhat effective, but only with long reaction times
3e [14][b]
3e [0]
3e [38] (18)
[a] Determined from the GLC peak area. The isolated yield is in
parentheses. [b] Complex mixture.
Next, we focused our attention on some enophiles pos-
at low temperature (Table 4, Entries 2–4). EtAlCl2 gave low sessing a neat formyl group. The reaction of aliphatic and
conversion to 3d together with 22% of the double-bond aromatic aldehydes with alkenes could be promoted by
isomerization product (E)-ethyl 6-[(tert-butyldimethyl- Me2AlCl.[17] We also found out that the reaction of 1 with
silyl)oxy]-2-hydroxy-4-methyl-2-(trifluoromethyl)-hex-4- 2,3,4,5,6-pentafluorobenzaldehyde (2f) was better effected
enoate (Table 4, Entry 5). The conversion was improved with EtAlCl2 or Me2AlCl than with SnCl4 (Table 6).
with Me2AlCl, though minor amounts of both the depro- Among the former two, Me2AlCl provided a moderate
tected and isomerized 3d were also obtained (Table 4, En- combined yield of the methylidenic alcohol 3f and depro-
try 6).
tected diol 4f (Table 6, Entry 3). It is also worth mentioning
Little has been studied about diethyl 2-oxomalonate (2e) that this reaction could easily be scaled to 5 mmol.
as an enophile in comparison with (CHO)n or the other
A similar trend to that mentioned above for 2f was ob-
2-oxoesters.[19] The resulting α-hydroxymalonic esters, once served when using 6-nitropiperonal (2g) as the enophile, al-
hydrolyzed, can undergo oxidative bis(decarboxylation), the though an intractable crude reaction mixture was obtained
entire sequence being synthetically equivalent to an ene re- with SnCl4 (Table 7, Entry 1). In this case, EtAlCl2 provided
action of carbon dioxide. Very low conversions were noted slightly better results than Me2AlCl, with the in situ depro-
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FULL PAPER
Table 6. Carbonyl-ene reaction of 1 with 2,3,4,5,6-pentafluorobenz- stead of in methanol to prevent transesterification (Table 8,
aldehyde (2f).
Entries 2–5). Perhydrofurofurans 5b–5d were obtained in
moderate yields and stereoselectivity favoring the (2R*,3a-
S*,6aR*)-5b, (2S*,3aS*,6aR*)-5c, and (2S*,3aS*,6aR*)-5d
diastereomers (Table 8, Entries 2–4). In these examples, the
differences in their moderate stereoselectivities follow simi-
Entry Lewis acid
[mol-%]
1/2f
[mmol] [°C]
T
t
Product[a]
larly to the trend of the differences in steric contribution of
the two substituents at the 2-position of the bicycle, that is,
CO2Et versus H in 5b gave higher a diastereomeric ratio
than CO2Et versus Me or CF3 in 5c and 5d, respectively.
Perhydrofurofuran-2,2-dicarboxylate (5e) was also success-
fully prepared in moderate yield from the diol (4e) derived
from diethyl 2-oxomalonate (Table 8, Entry 5). The more
sterically demanding pentafluorophenyl and 6-ni-
trobenzo[d][1,3]dioxol-5-yl groups imparted a higher dia-
stereoselectivity to perhydrofurofurans 5f and 5g, respec-
tively, with the latter achieving a maximum ratio of 87:13
also in favor of the (2R*,3aS*,6aR*) diastereomer (Table 8,
Entries 6 and 7). In general, equal or longer reaction times
were needed to get high conversions, in comparison to the
hydrocarbon-substituted analogs previously synthesized by
us.[9,10]
[h] [%]
1
2
3
SnCl4 [100]
1:1
1:1
1:1
0
24 1 [46], 3f [20],
4f [24][b]
EtAlCl2 [220]
Me2AlCl [220]
0 to r.t. 1.5 1 [8], 3f [64] (38),
4f [10] (8)[b]
0 to r.t. 27 1 [11], 3f [64] (55),
4f [25] (10)[b]
[a] Determined from the GLC peak area. The isolated yield is in
parentheses. [b] Deprotected 3f.
tection to the corresponding diol giving the highest re-
corded conversions amongst all the enophiles presently
tested (Table 7, Entries 2 and 3).
Table 7. Carbonyl-ene reaction of 1 with 6-nitropiperonal (2g).
The major relative configuration (2R*,3aS*,6aR*) ob-
served for 5b, 5f, and 5g is in agreement with what we re-
ported for 2,5-disubstituted and 2-monosubstituted perhy-
[9,10]
drofuro[2,3-b]furans
and was confirmed by NOE ex-
periments conducted on both diastereomers of compound
5b (Figure 2). A small NOE was observed for 2-H and 3a-
H in both diastereomers, whereas the NOE between 2-H
and 5-H was manifested in only the major diastereomer.
Analogous to the perhydrofurofuran bearing a phenyl
group at the 2-position,[10] the 2-H and 5-H in (2R*,3a-
S*,6aR*)-5b are believed to be in closer proximity than
those in (2S*,3aS*,6aR*)-5b, which would explain the
shown NOE (Figure 2). As shown earlier, we reported that
the opposite stereoselectivity was exhibited by 5c and 5d,
Entry Lewis acid
[mol-%]
1/2g
[mmol] [°C]
T
t
[h]
Product[a]
[%]
1
2
SnCl4 [100]
Me2AlCl [220]
1:1
1:1
–78
0 to r.t.
44
24
complex mixture
1 [10], 3g [21],
4g [69][b]
3
EtAlCl2 [220]
1:1
0 to r.t.
1
3g [31] (18),
4g [69] (30)[b]
[a] Determined from the GLC peak area. The isolated yield is in
parentheses. [b] Deprotected 3g.
The next step of the synthetic sequence was to submit all favoring the (2S*,3aS*,6aR*) diastereomer. Similarly, the
compounds 3 to deprotection. Using mild conditions and stereochemistry was established on the basis of NOE ex-
distinct reaction times, tetra-n-butylammonium fluoride periments performed on compound 5c. As depicted in Fig-
(TBAF) in THF (tetrahydrofuran) was used for this pur- ure 3, the NOE between the 5-H and 2-Me in (2R*,3a-
pose (Table 8).[20] Conversion to homoallylic alcohols 4 was S*,6aR*)-5c is in accordance with the short interatomic dis-
quantitative with the exception of compound 3e (60%). The tance measured in its geometry-optimized model (PM3 se-
isolated yields of 4 ranged from modest to good (47–71%) miempirical method was applied).[22] In contrast, this par-
as a result of the loss of mass during workup and/or purifi- ticular NOE was not detected for the major diastereomer
cation (Table 8). With a series of methylidenic diols 4 in (2S*,3aS*,6aR*)-5c, where the mentioned nuclei are further
hand, we studied their palladium-catalyzed intramolecular apart. The stereochemistry of 5d with the bulkier trifluoro-
acetalization reactions under Wacker-type conditions which methyl group could be rationalized likewise.
we previously developed.[9,10] The simplest diol, 3-methyl-
It is worth mentioning that the relative stereochemistry
enepentane-1,5-diol (4a), was transformed to the unsubsti- of compounds 5 could be correlated with the 1H NMR
tuted perhydrofuro[2,3-b]furan 5a in high conversion chemical shift of acetal hydrogen 6a-H (Table 9). In all
(Table 8, Entry 1). The low isolated yield attained was at- cases, 6a-H appeared more deshielded in (2R*,3aS*,6aR*)-
tributed to the compound’s high volatility. This represents 5 than in (2S*,3aS*,6aR*)-5, with chemical shift ranges of
the third synthesis of 5a. Previous ones involved the reac- 5.87–6.02 and 5.75–5.95 ppm, respectively. Furthermore,
tion of α-litioacetonitrile with protected 2-bromoethanol the differences in chemical shifts were larger (approximately
followed by deprotection and acetalization,[5a] and the rho- double Δδ) in the 2-monosubstituted series (Table 9, En-
dium-catalyzed hydroformylation–acetalization reaction of tries 1, 4, and 5) than in the 2,2-disubstituted derivatives
alkenediols.[21] It must be noted that the reactions with ethyl (Table 9, Entries 2 and 3). Indeed, this seems to be a direct
oxoester derivatives 4b–4e were carried out in ethanol in- and reliable method to assign the relative stereochemistry
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Synthesis of Perhydrofuro[2,3-b]furans from Isopentenyl Alcohol
Table 8. Synthesis of methylidenic diols 4 and perhydrofuro[2,3-b]furans 5.[a]
[a] Reagents and conditions: 3 (1 mmol), TBAF (1.58 mmol), THF, 0 °C to r.t.; 4 (1 mmol), PdCl2 (5 mol-%), CuCl2 (50 mol-%), 35%
H2O2 (10 mmol), MeOH (10 mL, Entries 1, 6, and 7) or EtOH (10 mL, Entries 2–5). [b] Isolated yield. [c] Conversion into 5 determined
1
by GLC. The GLC yield is in parentheses. The diastereomeric ratio was determined by H NMR spectroscopy. [d] The yield was deter-
1
mined by H NMR spectroscopy.
of 2-substituted perhydrofuro[2,3-b]furans (whenever both
A reaction mechanism for this palladium-catalyzed intra-
diastereomers are available), as the same trend was ob- molecular acetalization was proposed in our original contri-
served for perhydrofuro[2,3-b]furans with a hydrocarbon bution,[9] in terms of oxypalladation–dehydropalladation
substituent at the 2-position[10] and 2,5-positions.[7d]
reactions.[23] We rationalized the differences in the dia-
Eur. J. Org. Chem. 2011, 6459–6469
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F. Alonso, M. Rodríguez-Fernández, D. Sánchez, M. Yus
FULL PAPER
Figure 2. NOE experiments for the diastereomers of 5b.
Table 9. 1H NMR chemical shifts of 6a-H in (2R*,3aS*,6aR*)-5
and (2S*,3aS*,6aR*)-5.[a]
Entry Compound 5 δ(2R*,3aS*,6aR*) δ(2S*,3aS*,6aR*)
Δδ
[ppm]
[ppm]
[ppm]
1
2
3
4
5
5b
5c
5d
5f
5.91
5.87
6.02
5.91
5.97
5.77
5.79
5.95
5.75
5.82
0.14
0.08
0.07
0.16
0.15
5g
Figure 3. NOE experiments and optimized-geometry models for
the diastereomers of 5c. Numbers on the arrows refer to in-
teratomic distances in Å. Some hydrogen atoms have been omitted
for clarity.
[a] Chemical shifts were recorded at 400 MHz using CDCl3 as the
solvent and TMS as the internal standard.
stereoselectivity observed between the 2-monosubstituted
and 2,5-disubstituted perhydrofurofurans. The dia-
stereomeric ratios of the former with hydrocarbon substitu- and IX, resulting from the first cyclization, were proposed
ents (85:15–93:7)[10] were akin to those reported here followed by the corresponding hypothetical transition states
(76:24–87:13), but in both cases lower than those obtained VII and X, suggested for the second cyclization (Scheme 2).
for the 2,5-disubstituted derivatives (94:6–99:1).[9] In the lat- Unfavorable steric interactions involving the two R groups
ter case, two plausible π-palladium hydride complexes VI in transition state VII, which are absent in X, could account
Scheme 2. Intermediates and transition states proposed to explain the diastereoselectivity in the synthesis of 2,5-disubstituted and 2-
monosubstituted perhydrofuro[2,3-b]furans.
6464
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Eur. J. Org. Chem. 2011, 6459–6469

Synthesis of Perhydrofuro[2,3-b]furans from Isopentenyl Alcohol
Retention times (tR) are given in min. Flash column chromatog-
raphy was performed using silica gel 60 (40–60 microns).
for the preferential formation of perhydrofurofuran β-cis-6
through intermediate XI. A similar argument was invoked
to explain that β-cis-5 was the major diastereomer in the 2-
substituted perhydrofurofuran series. However, in this case
the energy difference between the hypothetical transition
states XIII and XVI must be lower than between those for
VII and X, and thus, there is a decrease in the diastereo-
selectivity.
General Procedures for the Carbonyl-Ene Reaction
Method A:[17] The Lewis acid solution (Me2AlCl or EtAlCl2,
2.2 mmol) was added, using a syringe and under nitrogen, to a
solution of the enophile (2, 1 mmol) and the protected isopentenyl
alcohol (1, 0.2 g, 1 mmol) in dry CH2Cl2 (5 mL) cooled in an ice
bath. After the addition, the ice bath was removed, and the solution
was stirred and monitored by GLC and/or TLC. Workup was per-
formed by slowly adding a saturated aqueous solution of NaH2PO4
(5 mL) and of Et2O (10 mL) to the reaction mixture. The dropwise
addition of 10% HCl dissolved the precipitated alumina. The or-
ganic layer was separated by decantation, the aqueous phase was
extracted with Et2O (3ϫ10 mL), and the combined organic layers
were dried with anhydrous MgSO4. The solvents were evaporated
in vacuo, and the residue obtained was subjected to flash
chromatography (silica gel, hexane/EtOAc) to yield the correspond-
ing ene adducts 3.
Conclusions
We have devised a new route toward the synthesis of per-
hydrofuro[2,3-b]furans consisting of: (1) protection of isop-
entenyl alcohol, (b) carbonyl-ene reaction with paraformal-
dehyde and various activated enophiles, (c) alcohol depro-
tection, and (d) palladium-catalyzed intramolecular acetali-
zation under Wacker-type reaction conditions. In the ene
reaction, tin(IV) chloride was the Lewis acid of choice for Method B:[24] In a dropwise manner, SnCl4 (0.12 mL, 1 mmol) was
added to a stirred solution of the appropriate enophile (2, 1 mmol)
and protected isopentenyl alcohol (1, 0.2 g, 1 mmol) in dry CH2Cl2
(5 mL) at –78 °C. The mixture was stirred at this temperature for
the time indicated in Tables 1, 2, 3, 4, 5, 6, and 7. Saturated aque-
ous NaHCO3 (3 mL) was then added, and the mixture was warmed
to room temperature before being partitioned between CH2Cl2 and
water. The organic extract was washed with brine and dried with
anhydrous MgSO4. Removal of the solvent under reduced pressure
followed by flash chromatography (silica gel, hexane/EtOAc)
yielded the corresponding ene adducts 3.
ethyl glyoxylate, ethyl pyruvate, and ethyl 2-oxomalonate,
whereas dimethylaluminium chloride worked better for pa-
raformaldehyde, ethyl trifluoropyruvate, and pentafluo-
robenzaldehyde, and ethylaluminium dichloride was best
for 6-nitropiperonal. The resulting homoallylic diols were
transformed into the corresponding perhydrofurofurans in
modest yields and variable diastereoselectivities which were
lower than those found for the 2,5-disubstituted analogs.
The relative stereochemistry of the perhydrofurofurans was
unequivocally established on the basis of NOE experiments.
5-(tert-Butyldimethylsilyloxy)-3-methylenepentan-1-ol (3a): Follow-
ing Method A (Table 1, Entry 8), compound 3a (166 mg, 72%) was
obtained as a colorless oil. Rf = 0.28 (hexane/EtOAc, 10:1); tR
=
11.89 min. 1H NMR (300 MHz, CDCl3): δ = 4.92 (s, 2 H, CH2=C),
3.76 (t, J = 6.7 Hz, 2 H, CH2OH), 3.73 (t, J = 6.2 Hz, 2 H,
CH2OTBDMS), 2.33 (t, J = 6.2 Hz, 2 H, CH2CH2OTBDMS), 2.28
(t, J = 6.7 Hz, 2 H, CH2CH2OH), 0.90 [s, 9 H, (CH3)3C], 0.07 [s,
6 H, (CH3)2Si] ppm. 13C NMR (75 MHz, CDCl3): δ = 143.6
(C=CH2), 113.7 (CH2=C), 62.4 (CH2OH), 60.6 (CH2OTBDMS),
39.6 (CH2CH2OH), 38.8 (CH2CH2OTBDMS), 25.9 [(CH3)3C],
Experimental Section
General Comments: Dimethylaluminium chloride (1.0 m solution in
hexane) and ethylaluminium dichloride (1.0 m solution in hexane)
were purchased from Aldrich. Tin(IV) chloride, 3-methylbut-3-en-
1-ol, paraformaldehyde, ethyl pyruvate, ethyl 3,3,3-trifluoropyruv-
ate, diethyl oxomalonate, 2,3,4,5,6-pentafluorobenzaldehyde, and
6-nitropiperonal were commercially available as the best grade (Al-
drich and Alfa Aesar) and were used without further purification.
Ethyl glyoxylate (50% in toluene, Aldrich) was distilled prior to
use. Dry THF and dichloromethane were dried in a Sharlab PS-
400–3MD solvent purification system using an alumina column.
Tetra-n-butylammonium fluoride (1.0 m solution in THF) was pur-
chased from Alfa Aesar. Infrared analysis was performed with a
FTIR Nicolet Impact 400D and Jasco 4100LE (Pike MIRacle
ATR) spectrophotometers, and wavenumbers are given in cm–1.
NMR spectroscopic data were recorded with Bruker Avance 300
and 400 spectrometers (300 and 400 MHz for 1H NMR, 75 and
100 MHz for 13C NMR) using CDCl3 as the solvent and TMS as
the internal standard. Chemical shifts are given in parts per million
(δ), and coupling constants are given in Hertz (J). Mass spectra
(EI) were obtained at 70 eV with an Agilent 5973 spectrometer,
and fragment ions are given in m/z with relative intensities (%) in
parenthesis. HRMS analyses were carried out with 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 ionization de-
tector and a 30 m capillary column (0.32 mm diameter, 0.25 μm
film thickness) using nitrogen (2 mL/min) as the carrier gas [Tinjector
= 275 °C, Tcolumn = 60 °C (3 min) and then 60–270 °C (15 °C/min)].
18.3 [C(CH ) ], –5.4 [(CH ) Si] ppm. IR (CCl ): ν = 3362, 1256,
˜
3 3
3 2
4
1047, 870, 836 cm–1. MS (EI): m/z (%) = 229 (Ͻ1%) [M – H]+, 144
(13), 143 (100), 105 (13), 101 (36), 89 (11), 75 (46), 73 (19). HRMS
(EI): calcd. for C12H25SiO2 [M – H]+ 229.1624; found 229.1624.
Ethyl
6-(tert-Butyldimethylsilyloxy)-2-hydroxy-4-methylenehex-
anoate (3b): Following Method B (Table 2, Entry 8), compound 3b
(200 mg, 66%) was obtained as a colorless oil. Rf = 0.25 (hexane/
EtOAc, 10:1); tR = 14.84 min. 1H NMR (300 MHz, CDCl3): δ =
4.94 (s, 2 H, CH2=C), 4.34 (ddd, J = 8.4, 5.2, 3.9 Hz, 1 H, CHOH),
4.25 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.76 (t, J = 6.7 Hz, 2 H,
CH2OTBDMS), 2.95 (d, J = 5.2 Hz, 1 H, OH), 2.61 (dd, J = 14.2,
3.9 Hz, 1 H, CHHCH), 2.38 (dd, J = 14.2, 8.4 Hz, 1 H, CHHCH),
2.32 (t, J = 6.7 Hz, 2 H, CH2CH2O), 1.31 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 0.90 [s, 9 H, (CH3)3C], 0.07 [s, 6 H, (CH3)2Si] ppm.
13C NMR (75 MHz, CDCl3): δ = 174.5 (CO2), 142.4 (C=CH2),
114.8 (CH2=C), 69.5 (CHCH2), 62.4 (OCH2CH3), 61.6
(CH2OTBDMS), 41.4 (CH2CH), 39.0 (CH2CH2O), 25.9 [(CH3)3C],
18.3 [C(CH3)3], 14.2 (CH3CH2O), –5.4 [(CH3)2Si] ppm. IR (CCl4):
ν = 3415, 1738, 1259, 1099 cm–1. MS (EI): m/z (%) = 257 (4) [M –
˜
C2H5O]+, 227 (15), 215 (100), 171 (69), 143 (41), 141 (39), 131 (26),
103 (20), 101 (19), 97 (20), 89 (23), 75 (86), 73 (42). HRMS (EI):
calcd. for C13H25SiO3 [M – C2H5O]+ 257.1573; found 257.1589.
Eur. J. Org. Chem. 2011, 6459–6469
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6465

F. Alonso, M. Rodríguez-Fernández, D. Sánchez, M. Yus
FULL PAPER
Ethyl 6-(tert-Butyldimethylsilyloxy)-2-hydroxy-2-methyl-4-methyl-
enehexanoate (3c): Following Method B (Table 3, Entry 3), com-
pound 3c (130 mg, 40%) was obtained with 4c (28 mg, 14%) as a
J = 6.2 Hz, 2 H, CH2CH2O), 0.91 [s, 9 H, (CH3)3C], 0.09 [s, 6 H,
1
(CH3)2Si] ppm. 13C NMR (100 MHz, CDCl3): δ = 144.8 (d, JC,F
1
= 251.0 Hz, ArCF), 142.7 (C=CH2), 140.5 (d, JC,F = 253.5 Hz,
1
1
colorless oil. Rf = 0.35 (hexane/EtOAc, 15:1); tR = 14.83 min. H
ArCF), 137.5 (d, JC,F = 253.5 Hz, ArCF), 116.7 (ArC), 115.7
NMR (400 MHz, CDCl3): δ = 4.87, 4.81 (2 s, 2 H, CH2=C), 4.17,
4.15 (2 dq, J = 10.5, 7.1 Hz, 2 H, OCH2CH3), 3.66 (t, J = 6.8 Hz,
2 H, CH2OTBDMS), 2.53, 2.33 (2 d, J = 13.8 Hz, 2 H, CCH2C),
2.28, 2.22 (2 dt, J = 14.7, 6.8 Hz, 2 H, CH2CH2O), 1.37 (s, 3 H,
CCH3), 1.25 (t, J = 7.1 Hz, 3 H, CH3CH2O), 0.84 [s, 9 H, (CH3)3-
C], 0.01 [s, 6 H, (CH3)2Si] ppm. 13C NMR (75 MHz, CDCl3): δ =
(CH2=C), 64.8 (CHCH2), 62.5 (CH2OTBDMS), 43.8 (CH2CH),
38.6 (CH2CH2O), 25.9 [(CH3)3C], 18.3 [C(CH3)3], –5.4 [(CH3)2-
Si] ppm. IR (CCl ): ν = 3405, 1652, 1304, 1257, 1121, 837,
˜
4
778 cm–1. MS (EI): m/z (%) = 396 (Ͻ1%) [M]+, 339 (11), 337 (11),
321 (31), 247 (13), 219 (21), 197 (43), 181 (43), 167 (7), 143 (17),
127 (13), 105 (100), 101 (19), 75 (84). HRMS (EI): calcd. for
176.6 (CO2), 142.4 (C=CH2), 115.7 (CH2=C), 74.8 (COH), 62.3 C14H16SiO2F5 [M – C4H9]+ 339.0840; found 339.0843.
(OCH2CH3), 61.6 (CH2OTBDMS), 46.2 (CCH2C), 40.0
5-(tert-Butyldimethylsilyloxy)-3-methylene-1-(6-nitrobenzo[d][1,3]-
(CH2CH2O), 26.4 (CH3C), 25.9 [(CH3)3C], 18.3 [C(CH3)3], 14.2
dioxol-5-yl)pentan-1-ol (3g): Following Method A (Table 7, En-
(CH CH O), –5.3 [(CH ) Si] ppm. IR (CCl ): ν = 3435, 1733, 1698,
˜
3
2
3 2
4
try 3), compound 3g (71 mg, 18%) was obtained with 4g (84 mg,
30%) as an orange oil; Rf = 0.27 (hexane/EtOAc, 5:1). H NMR δ
1255, 1205, 1109, 837 cm–1. MS (EI): m/z (%) = 316 (Ͻ1%) [M]+,
229 (32), 185 (96), 183 (33), 145 (32), 111 (53), 89 (33), 75 (100),
73 (61). HRMS (EI): calcd. for C14H27SiO3 [M – C2H5O]+
271.1729; found 271.1717.
1
= (300 MHz, CDCl3): 7.50, 7.34 (2 s, 2 H, 2 ArH), 6.11 (s, 2 H,
OCH2O), 5.43 (dd, J = 9.8, 2.4 Hz, 1 H, CHOH), 5.09, 5.06 (2 s,
2 H, CH2=C), 3.86 (td, J = 6.3, 2.8 Hz, 2 H, CH2OTBDMS), 2.72
(d, J = 13.7 Hz, 1 H, CHHCH), 2.41 (t, J = 6.3 Hz, 2 H,
CH2CH2O), 2.19 (dd, J = 13.7, 9.8 Hz, 1 H, CHHCH), 0.90 [s, 9
H, (CH3)3C], 0.08 [s, 6 H, (CH3)2Si] ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.4, 146.7, 143.5, 137.9 (4 ArC), 141.1 (C=CH2),
115.9 (CH2=C), 106.9, 105.1 (2 ArCH), 102.8 (OCH2O), 67.6
(CHOH), 62.2 (CH2OTBDMS), 46.3 (CH2CH), 38.3 (CH2CH2O),
Ethyl 6-(tert-Butyldimethylsilyloxy)-2-hydroxy-4-methylene-2-(tri-
fluoromethyl)hexanoate (3d): Following Method A (Table 4, En-
try 6), compound 3d (44 mg, 12%) was obtained with 4d (15 mg,
6%) as a colorless oil. Rf = 0.28 (hexane/EtOAc, 10:1); tR
=
1
14.09 min. H NMR (300 MHz, CDCl3): δ = 4.97, 4.94 (2 s, 2 H,
CH2=C), 4.36, 4.32 (2 dq, J = 10.6, 7.1 Hz, 2 H, OCH2CH3), 3.74
(td, J = 6.4, 2.0 Hz, 2 H, CH2OTBDMS), 2.80, 2.69 (2 d, J =
14.1 Hz, 2 H, CCH2C), 2.42, 2.29 (2 dt, J = 14.6, 6.4 Hz, 2 H,
CH2CH2O), 1.35 (t, J = 7.1 Hz, 3 H, CH3CH2O), 0.91 [s, 9 H,
25.9 [(CH ) C], 18.4 [C(CH ) ], –5.3 [(CH ) Si] ppm. IR (CCl ): ν
˜
3 3
3 3
3 2
4
= 3411, 1618, 1483, 1332, 1256, 1097, 1038, 933, 836 cm–1. MS [EI-
DIP (direct insertion probe)]: m/z (%) = 395 (Ͻ1%) [M]+, 278 (16),
220 (23), 196 (32), 143 (50), 131 (31), 75 (60), 69 (100). HRMS (EI-
DIP): calcd. for C19H29NSiO6 [M]+ 395.1764; found 395.1795.
(CH3)3C], 0.08 [s, 6 H, (CH3)2Si] ppm. 13C NMR (100 MHz,
1
CDCl3): δ = 169.2 (CO2), 140.3 (C=CH2), 123.3 (q, JC,F
=
2
287.0 Hz, CF3), 116.9 (CH2=C), 78.4 (q, JC,F = 28.6 Hz, CCF3),
63.4 (OCH2CH3), 62.4 (CH2OTBDMS), 39.9 (CCH2C), 37.4
(CH2CH2O), 25.9 [(CH3)3C], 18.3 [C(CH3)3], 14.0 (CH3CH2O),
General Procedure for the Deprotection of Homoallylic Alcohols
3:[20] TBAF (1.58 mmol) was added to a stirred solution of diol 3
(1 mmol) in dry THF (33 mL) previously cooled in an ice bath.
The ice bath was removed, and the reaction solution was stirred
and monitored by GLC or TLC. Silica gel was added to the re-
sulting mixture followed by solvent evaporation and flash
chromatography (silica gel, hexane/EtOAc).
–5.4 [(CH ) Si] ppm. IR (CCl ): ν = 3494, 1742, 1310, 1251, 1128,
˜
3 2
4
1099, 836, 776, 697 cm–1. MS (EI): m/z (%) = 325 (4) [M –
C2H5O]+, 295 (22), 283 (100), 255 (25), 107 (25), 99 (26), 97 (21),
95 (23), 89 (52), 80 (25), 77 (81), 75 (54), 73 (85), 67 (24). HRMS
(EI): calcd. for C14H24SiO3F3 [M – C2H5O]+ 325.1447; found
325.1452.
3-Methylidenepentane-1,5-diol (4a):[17] Colorless liquid; Rf = 0.23
1
(hexane/EtOAc, 1:4); tR = 7.86 min. H NMR (300 MHz, CDCl3):
Diethyl
2-[4-(tert-Butyldimethylsilyloxy)-2-methylenebutyl]-2-hy-
δ = 5.00 (s, 2 H, CH2=C), 3.78 (t, J = 6.2 Hz, 4 H, 2 CH2OH),
2.35 (t, J = 6.2 Hz, 4 H, 2 CH2CH2OH), 1.64 (br. s, 2 H, 2
OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.3 (C=CH2), 113.3
(CH2=C), 60.4 (2 CH2OH), 38.8 (2 CH2CH2OH) ppm. IR (CCl4):
droxymalonate (3e): Following Method B (Table 5, Entry 6), com-
pound 3e (67 mg, 18%) was obtained as a colorless oil. Rf = 0.27
(hexane/EtOAc, 15:1); tR = 15.45 min. 1H NMR (400 MHz,
CDCl3): δ = 4.90 (s, 2 H, CH2=C), 4.24 (q, J = 7.1 Hz, 4 H, 2
CH2CH3), 3.70 (t, J = 6.7 Hz, 2 H, CH2OTBDMS), 2.82 (s, 2 H,
CCH2C), 2.32 (t, J = 6.7 Hz, 2 H, CH2CH2O), 1.28 (t, J = 7.1 Hz,
6 H, 2 CH3CH2), 0.88 [s, 9 H, (CH3)3C], 0.04 [s, 6 H, (CH3)2-
Si] ppm. 13C NMR (75 MHz, CDCl3): δ = 170.1 (2 CO2), 141.2
(C=CH2), 115.9 (CH2=C), 79.3 (COH), 62.3 (2 CH2CH3), 62.1
(CH2OTBDMS), 40.2 (CCH2C), 40.1 (CH2CH2O), 25.8 [(CH3)3C],
18.2 [C(CH3)3], 14.0 (2 CH3CH2), –5.4 [(CH3)2Si] ppm. IR (CCl4):
ν = 3362, 3077, 1645, 1046, 897 cm–1. MS (EI): m/z (%) = 116
˜
(Ͻ1%) [M]+, 98 (5), 86 (32), 69 (28), 68 (87), 67 (100), 56 (44), 53
(36). HRMS (EI): calcd. for C6H10O [M – H2O]+ 98.0732; found
98.0731.
Ethyl 2,6-Dihydroxy-4-methylidenehexanoate (4b): Colorless oil; Rf
1
= 0.38 (hexane/EtOAc, 1:4); tR = 11.11 min. H NMR (300 MHz,
CDCl3): δ = 5.01 (s, 2 H, CH2=C), 4.35 (dd, J = 8.4, 4.1 Hz, 1 H,
CHOH), 4.25 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.76 (t, J = 6.2 Hz,
2 H, CH2OH), 2.60 (dd, J = 14.5, 4.1 Hz, 1 H, CHHCH), 2.38 (dd,
J = 14.5, 8.4 Hz, 1 H, CHHCH), 2.37 (t, J = 6.2 Hz, 2 H,
CH2CH2O), 1.31 (t, J = 7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR
(75 MHz, CDCl3): δ = 174.5 (CO2), 141.7 (C=CH2), 115.5
ν = 3495, 2857, 1740, 1255, 1214, 1081, 837 cm–1. MS (EI): m/z
˜
(%) = 374 (Ͻ1%) [M]+, 287 (56), 243 (33), 215 (54), 189 (87), 95
(42), 89 (32), 75 (100). HRMS (EI): calcd. for C16H29SiO5 [M –
C2H5O]+ 329.1784; found 329.1783.
5-(tert-Butyldimethylsilyloxy)-3-methylene-1-(pentafluorophenyl)- (CH2=C), 69.7 (CHCH2), 61.8 (OCH2CH3), 60.6 (CH2OH), 40.5
pentan-1-ol (3f): Following Method A (Table 6, Entry 3), com-
pound 3f (218 mg, 55%) was obtained with 4f (28 mg, 10%) as a
colorless oil. Rf = 0.35 (hexane/EtOAc, 10:1); tR = 15.85 min. H
NMR (300 MHz, CDCl3): δ = 5.25 (dd, J = 9.5, 4.9 Hz, 1 H,
CHOH), 4.99, 4.98 (2 s, 2 H, CH2=C), 3.82 (t, J = 6.2 Hz, 2 H,
CH2OTBDMS), 3.15 (br. s, 1 H, OH), 2.82 (dd, J = 13.8, 9.5 Hz,
(CH2CH), 39.1 (CH2CH2O), 14.1 (CH3CH2O) ppm. IR [ATR, (at-
tenuated total reflectance)]: ν = 3403, 1735, 1647, 1269, 1100,
˜
1041 cm–1. MS (EI): m/z (%) = 188 (Ͻ1%) [M]+, 170 (3), 158 (20),
140 (53), 113 (22), 112 (40), 111 (24), 97 (61), 96 (34), 95 (24), 85
(25), 79 (21), 75 (24), 69 (100), 57 (27), 56 (33), 55 (38), 53 (27).
HRMS (EI): calcd. for C9H15O3 [M – OH]+ 171.1021; found
1
1 H, CHHCH), 2.53 (dd, J = 13.8, 4.9 Hz, 1 H, CHHCH), 2.34 (t, 171.1002.
6466
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6459–6469

Synthesis of Perhydrofuro[2,3-b]furans from Isopentenyl Alcohol
Ethyl 2,6-Dihydroxy-2-methyl-4-methylidenehexanoate (4c): Color-
13.9 Hz, 1 H, CHHCH), 2.45 (t, J = 6.1 Hz, 2 H, CH2CH2OH),
2.19 (dd, J = 13.9, 9.9 Hz, 1 H, CHHCH) ppm. 13C NMR
1
less oil; Rf = 0.40 (hexane/EtOAc, 1:2); tR = 11.03 min. H NMR
(300 MHz, CDCl3): δ = 4.97, 4.91 (2 s, 2 H, CH2=C), 4.17, 4.15 (2 (75 MHz, CDCl3): δ = 152.4, 146.8, 143.0, 138.1 (4 ArC), 140.9
dq, J = 10.5, 7.1 Hz, 2 H, OCH2CH3), 3.71 (t, J = 6.1 Hz, 2 H, (C=CH2), 115.8 (CH2=C), 106.7, 105.1 (2 ArCH), 102.9 (OCH2O),
CH2OH), 3.54 (s, 1 H, OH), 2.57, 2.41 (2 d, J = 14.0 Hz, 2 H, 67.7 (CHOH), 60.7 (CH2OH), 45.4 (CH2CH), 38.2
CCH2C), 2.39, 2.32 (2 dt, J = 14.4, 6.1 Hz, 2 H, CH2CH2O), 2.08 (CH CH OH) ppm. IR (CCl ): ν = 3373, 1519, 1330, 1120, 930,
˜
2
2
4
(br. s, 1 H, OH), 1.42 (s, 3 H, CCH3), 1.30 (t, J = 7.1 Hz, 3 H,
760 cm–1. MS (EI-DIP): m/z (%) = 263 (Ͻ1%) [M – H2O]+, 230
CH3CH2O) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.6 (CO2), (15), 195 (36), 187 (20), 165 (87), 148 (37), 134 (14), 127 (15), 120
142.0 (C=CH2), 116.2 (CH2=C), 75.0 (COH), 61.8 (OCH2CH3), (98), 119 (58), 107 (90), 103 (20), 79 (79), 63 (100), 62 (39). HRMS
60.7 (CH2OH), 45.3 (CCH2C), 39.9 (CH2CH2O), 26.6 (CCH3), (EI-DIP): calcd. for C13H15NO6 [M]+ 281.0899; found 281.0915.
14.1 (CH CH O) ppm. IR (CCl ): ν = 3384, 1731, 1644, 1206,
˜
3
2
4
General Procedure for the Intramolecular Acetalization of Homo-
allylic Diols 4: A solution of PdCl2 (8.9 mg, 0.05 mmol), CuCl2
(67.2 mg), and the corresponding methylidenic diol 4 (1 mmol) in
MeOH (10 mL, for 4a, 4f, and 4g) or EtOH (10 mL, for 4b–4e)
was prepared in a tube equipped with a screw top followed by the
addition of a 35% H2O2 solution (0.86 mL, 10 mmol). The top was
airtight on the reaction tube which was heated at 70 °C for 24 h.
After that time, the reaction progress was monitored by TLC and
GLC. One additional portion of the 35% H2O2 solution (0.86 mL,
10 mmol) along with heating (70 °C for 24 h) was required for 4c,
4e–4g (Table 8, Entries 3, 5, 6, and 7), and two portions were
needed for 4d (Table 8, Entry 5).
Workup for 5c, 5d, 5f, 5g: The solvent was evaporated to dryness
followed by the addition of EtOAc (20 mL) and filtration of the
resulting mixture through Celite. The filtrate was washed with brine
(2ϫ5 mL), the organic phase was dried with anhydrous MgSO4,
and the solvent was evaporated under vacuum. Workup for 5a, 5b,
5e: Brine (10 mL) was added to the reaction mixture followed by
extraction with CH2Cl2 (3ϫ20 mL). The organic phase was
washed with water (2ϫ10 mL) and filtered through Celite. The sol-
vent was evaporated under vacuum at 15 °C. All compounds 5,
except 5a, were purified by column chromatography (silica gel, hex-
ane/EtOAc).
1021 cm–1. MS (EI): m/z (%) = 202 (Ͻ1%) [M]+, 117 (100), 111
(75), 69 (38), 68 (33), 67 (48). HRMS (EI): calcd. for C10H18O4
[M]+ 202.1205; found 202.1189.
Ethyl
2,6-Dihydroxy-4-methylidene-2-(trifluoromethyl)hexanoate
(4d): Colorless oil; Rf = 0.40 (hexane/EtOAc, 1:1); tR = 11.19 min.
1H NMR (300 MHz, CDCl3): δ = 4.99, 4.97 (2 s, 2 H, CH2=C),
4.52 (s, 1 H, OH), 4.35, 4.28 (2 dq, J = 10.7, 7.1 Hz, 2 H,
OCH2CH3), 3.72 (t, J = 6.3 Hz, 2 H, CH2OH), 2.77, 2.64 (2 d, J
= 14.2 Hz, 2 H, CCH2C), 2.41, 2.32 (2 dt, J = 15.2, 6.3 Hz, 2 H,
CH2CH2O), 1.32 (t, J = 7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR
(75 MHz, CDCl3): δ = 169.2 (CO2), 139.6 (C=CH2), 123.2 (q, 1JC,F
= 287.0 Hz, CF3), 117.4 (CH2=C), 78.4 (q, 2JC,F = 28.6 Hz, CCF3),
63.7 (OCH2CH3), 60.6 (CH2OH), 39.8 (CCH2C), 36.8
(CH CH O), 13.9 (CH CH O) ppm. IR (CCl ): ν = 3479, 1744,
˜
2
2
3
2
4
1311, 1224, 1132, 699 cm–1. MS (EI): m/z (%) = 238 (5) [M –
H2O]+, 208 (55), 180 (100), 165 (48), 117 (29), 97 (28), 95 (37), 83
(28), 69 (43), 55 (48). HRMS (EI): calcd. for C10H13O3F3 [M –
H2O]+ 238.0817; found 238.0825.
Diethyl Hydroxy(4-hydroxy-2-methylidenebutyl)propanedioate (4e):
Colorless oil; Rf = 0.29 (hexane/EtOAc, 1:1); tR = 13.39 min. 1H
NMR (400 MHz, CDCl3): δ = 5.00 (s, 2 H, CH2=C), 4.27 (q, J =
7.1 Hz, 4 H, 2 CH2CH3), 3.75 (t, J = 6.0 Hz, 2 H, CH2OH), 2.84
(s, 2 H, CCH2C), 2.39 (t, J = 6.0 Hz, 2 H, CH2CH2O), 1.30 (t, J
= 7.1 Hz, 6 H, 2 CH3CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.1 (2 CO2), 140.8 (C=CH2), 116.8 (CH2=C), 79.4 (COH), 62.5
(2 CH2CH3), 60.5 (CH2OH), 40.1 (CCH2C), 39.4 (CH2CH2O), 14.0
cis-Perhydrofuro[2,3-b]furan (5a):[5a] Colorless oil; Rf = 0.33 (hex-
1
ane/EtOAc, 7:3); tR = 6.89 min. H NMR (300 MHz, CDCl3): δ =
5.68 (d, J = 5.1 Hz, 1 H, OCHO), 3.86 (dd, J = 9.0, 5.1 Hz, 4 H,
2 CH2O), 2.88–2.79 (m, 1 H, CH2CHCH2), 2.12–2.04, 1.73–1.69 (2
m, 4 H, CH2CHCH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 109.5
(OCHO), 68.1 (2 CH2O), 42.4 (CH2CHCH2), 32.5
(2 CH CH ) ppm. IR (CCl ): ν = 3496, 1739, 1266, 1210 cm–1. MS
˜
3
2
4
(EI): m/z (%) = 260 (Ͻ1%) [M]+, 242 (3) [M – H2O]+, 212 (72),
184 (42), 175 (28), 169 (82), 168 (34), 150 (29), 141 (21), 138 (45),
123 (39), 113 (35), 97 (24), 95 (100), 83 (90), 82 (27), 71 (21), 69
(27), 68 (23), 67 (85), 55 (61), 54 (21). HRMS (EI): calcd. for
C12H18O5 [M – H2O]+ 242.1154; found 242.1129.
(CH CHCH ) ppm. IR (film): ν = 1055, 1026 cm–1. MS (EI): m/z
˜
2
2
(%) = 114 (12) [M]+, 113 (30), 84 (95), 83 (32), 69 (49), 68 (68), 67
(68), 57 (13), 56 (46), 55 (100), 54 (26), 53 (25). HRMS (EI): calcd.
for C6H10O2 [M]+ 114.0681; found 114.0687.
3-Methylidene-1-(pentafluorophenyl)pentane-1,5-diol (4f): Colorless
oil; Rf = 0.23 (hexane/EtOAc, 1:1); tR = 13.79 min. 1H NMR
(300 MHz, CDCl3): δ = 5.23 (dd, J = 9.0, 5.3 Hz, 1 H, CHOH),
5.01, 5.00 (2 s, 2 H, CH2=C), 3.79 (t, J = 6.1 Hz, 2 H, CH2OH),
3.35 (br. s, 1 H, OH), 2.79 (dd, J = 14.0, 9.0 Hz, 1 H, CHHCH),
2.52 (dd, J = 14.0, 5.3 Hz, 1 H, CHHCH), 2.37, 2.34 (2 dt, J =
14.9, 6.1 Hz, 2 H, CH2CH2O) ppm. 13C NMR (75 MHz, CDCl3):
(2R*,3aS*,6aR*)-Ethyl
Perhydrofuro[2,3-b]furan-2-carboxylate
(5b): Colorless oil; Rf = 0.59 (hexane/EtOAc, 1:1); tR = 12.18 min.
1H NMR (400 MHz, CDCl3): δ = 5.91 (d, J = 5.0 Hz, 1 H, OCHO),
4.62 (t, J = 7.2 Hz, 1 H, OCHCO2), 4.18 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 3.95–3.84 (m, 2 H, OCH2CH2), 2.98–2.84 (m, 1 H,
CH2CHCH2), 2.25–2.14, 2.14–2.00, 1.76–1.68 (3 m,
CH2CHCH2), 1.26 (t, J = 7.2 Hz, 3 H, CH3CH2O) ppm. 13C NMR
(100 MHz, CDCl3): 172.1 (CO2), 110.2 (OCHO), 77.3
4 H,
1
δ = 144.7 (d, JC,F = 248.2 Hz, ArCF), 141.8 (C=CH2), 140.5 (d,
δ
=
1JC,F = 253.8 Hz, ArCF), 137.5 (d, 1JC,F = 253.2 Hz, ArCF), 116.6
(ArC), 115.9 (CH2=C), 64.6 (CHCH2), 60.7 (CH2OH), 43.1
(OCHCO2), 61.3 (OCH2CH3), 67.7 (OCH2CH2), 41.8
(CH2CHCH2), 35.9, 32.2 (CH2CHCH2), 14.2 (CH3CH2O) ppm. IR
(CH CH), 38.3 (CH CH O) ppm. IR (CCl ): ν = 3400, 1681, 1304,
˜
2
2
2
4
(film): ν = 1750, 1278, 1203, 1113, 1063, 1036 cm–1. MS (EI): m/z
˜
1146, 1124 cm–1. MS (EI): m/z (%) = 282 (Ͻ1%) [M]+, 264 (4), 246
(38), 234 (24), 197 (100), 181 (37), 169 (29), 68 (30), 67 (30). HRMS
(EI): calcd. for C12H9OF5 [M – H2O]+ 264.0574; found 264.0574.
(%) = 186 (Ͻ1%) [M]+, 113 (100), 69 (89), 66 (17), 55 (30). HRMS
(EI): calcd. for C9H14O4 [M]+ 186.0892; found 186.0895. Selected
data for the minor diastereomer (2S*,3aS*,6aR*)-5b: tR
=
1
3-Methylidene-1-(6-nitro-1,3-benzodioxol-5-yl)pentane-1,5-diol (4g):
11.98 min. H NMR (400 MHz, CDCl3): δ = 5.77 (d, J = 5.2 Hz,
Yellow oil; Rf = 0.26 (hexane/EtOAc, 1:1). 1H NMR (300 MHz, 1 H, OCHO), 4.44 (dd, J = 8.3, 6.7 Hz, 1 H, OCHCO2), 2.55–2.44,
CDCl3): δ = 7.49, 7.32 (2 s, 2 H, 2 ArH), 6.12, 6.11 (2 d, J = 1.2 Hz,
2 H, OCH2O), 5.45 (dd, J = 9.9, 2.4 Hz, 1 H, CHOH), 5.12, 5.09
(2 s, 2 H, CH2=C), 3.84 (t, J = 6.1 Hz, 2 H, CH2OH), 2.68 (d, J =
2.14–2.00, 1.99–1.89, 1.76–1.68 (4 m, 4 H, CH2CHCH2) ppm. MS
(EI): m/z (%) = 186 (Ͻ1%) [M]+, 113 (100), 69 (91), 67 (17), 55
(31).
Eur. J. Org. Chem. 2011, 6459–6469
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6467

F. Alonso, M. Rodríguez-Fernández, D. Sánchez, M. Yus
FULL PAPER
(2S*,3aS*,6aR*)-Ethyl 2-Methylperhydrofuro[2,3-b]furan-2-carb-
(3) [M]+, 235 (12), 234 (43), 233 (11), 219 (83), 214 (11), 207 (15),
195 (33), 194 (66), 193 (10), 187 (23), 181 (73), 169 (17), 167 (11),
143 (11), 84 (100), 83 (24), 69 (20), 56 (22), 55 (36), 54 (12). HRMS
(EI): calcd. for C12H9F5O2 [M]+ 280.0523; found 280.0519. Selected
oxylate (5c): Colorless oil; Rf = 0.54 (hexane/EtOAc, 1:1); tR
=
1
11.68 min. H NMR (400 MHz, CDCl3): δ = 5.79 (d, J = 5.1 Hz,
1 H, OCHO), 4.22 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.91–3.78 (m,
2 H, OCH2CH2), 3.01–2.86 (m, 1 H, CH2CHCH2), 2.42–2.33, data for the minor diastereomer (2S*,3aS*,6aR*)-5f: tR
=
1
2.11–1.99, 1.76–1.67 (3 m, 4 H, CH2CHCH2), 1.45 (s, 3 H, CH3C), 13.43 min. H NMR (400 MHz, CDCl3): δ = 5.75 (d, J = 5.5 Hz,
1.30 (t, J = 7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR (100 MHz, 1 H, OCHO), 5.10 (dd, J = 11.2, 5.8 Hz, 1 H, OCHAr), 3.08–2.98
CDCl3): δ = 174.6 (CO2), 110.4 (OCHO), 84.7 (CCH3), 67.2 (m, 1 H, CH2CHCH2) ppm. 13C NMR (100 MHz, CDCl3): δ =
(OCH2CH2), 61.4 (OCH2CH3), 42.9 (CH2CHCH2), 41.1, 32.0
(CH CHCH ), 23.9 (CH C), 14.3 (CH CH O) ppm. IR (film): ν =
109.3 (OCHO), 70.7 (OCHAr), 66.5 (OCH2 CH2 ), 43.4
(CH2CHCH2), 36.2, 32.6 (CH2CHCH2) ppm. MS (EI): m/z (%) =
280 (Ͻ1%) [M]+, 234 (15), 219 (43), 195 (27), 194 (42), 187 (15),
˜
2
2
3
3
2
1731, 1286, 1184, 1129, 1017 cm–1. MS (EI): m/z (%) = 156 (1) [M –
CO2]+, 127 (100), 85 (15), 83 (11), 81 (9). HRMS (EI): calcd. for 181 (47), 169 (11), 84 (100), 83 (22), 69 (16), 56 (19), 55 (31), 54
C10H16O4 [M]+ 200.1049; found 200.1048. Selected data for the
minor diastereomer (2R*,3aS*,6aR*)-5c: tR = 11.82 min. 1H NMR
(400 MHz, CDCl3): δ = 5.87 (d, J = 5.3 Hz, 1 H, OCHO), 4.18 (q,
J = 6.8 Hz, 2 H, OCH2CH3), 2.57–2.49, 2.08–1.89, 1.76–1.67 (3 m,
4 H, CH2CHCH2), 1.55 (s, 3 H, CH3C) ppm. MS (EI): m/z (%) =
156 (1) [M – CO2]+, 127 (100), 85 (15), 83 (9), 81 (10).
(11).
5-[(2R*,3aS*,6aR*)-Perhydrofuro[2,3-b]furan-2-yl]-6-nitro-1,3-benzo-
[d][1,3]dioxole (5g): Yellow oil; Rf = 0.64 (hexane/EtOAc, 1:1); tR
=
1
20.46 min. H NMR (400 MHz, CDCl3): δ = 7.52, 7.25 (2 s, 2 H,
2 ArH), 6.11 (d, J = 3.0 Hz, 2 H, OCH2O), 5.97 (d, J = 5.0 Hz, 1
H, OCHO), 5.65 (dd, J = 9.6, 5.6 Hz, 1 H, OCHAr), 4.08–3.94 (m,
2 H, OCH2CH2), 3.05–2.95 (m, 1 H, CH2CHCH2), 2.60–2.51,
2.25–2.13, 1.96–1.88, 1.88–1.78 (4 m, 4 H, CH2CHCH2) ppm. 13C
NMR (100 MHz, CDCl3): δ = 152.7, 147.1, 141.3, 136.2 (4 ArC),
109.5 (OCHO), 106.3, 105.4 (2 ArCH), 103.1 (OCH2O), 77.5
(OCHAr), 68.1 (OCH2CH2), 43.1 (CH2CHCH2), 41.0, 32.4
(2S*,3aS*,6aR*)-Ethyl 2-(Trifluoromethyl)perhydrofuro[2,3-b]fur-
an-2-carboxylate (5d): Colorless oil; Rf = 0.55 (hexane/EtOAc, 3:1);
tR = 10.48 min. 1H NMR (400 MHz, CDCl3): δ = 5.95 (d, J =
5.0 Hz, 1 H, OCHO), 4.32 (q, J = 7.0 Hz, 2 H, OCH2CH3), 4.04–
3.92 (m, 2 H, OCH2CH2), 3.10–2.97 (m, 1 H, CH2CHCH2), 2.73–
2.65, 2.30–1.99, 1.77–1.68 (3 m, 4 H, CH2CHCH2), 1.33 (t, J =
7.0 Hz, 3 H, CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ =
169.2 (CO2), 127.2 (CF3), 112.9 (OCHO), 84.7 (CCF3), 67.1
(OCH2CH2), 62.9 (OCH2CH3), 42.6 (CH2CHCH2), 36.1, 32.6
(CH CHCH ) ppm. IR (ATR): ν = 3018, 2853, 1512, 1482, 1257,
˜
2
2
1150, 1019 cm–1. MS (EI): m/z (%) = 262 (6) [M – OH]+, 216 (28),
206 (12), 190 (10), 187 (12), 178 (11), 177 (10), 176 (17), 174 (11),
164 (15), 163 (12), 149 (14), 148 (21), 136 (22), 135 (16), 120 (22),
119 (11), 115 (10), 84 (17), 83 (100), 79 (13), 77 (13), 70 (12), 69
(20), 65 (12), 63 (19), 62 (12), 56 (17), 55 (45), 54 (11), 53 (15),
51 (10). HRMS (EI): calcd. for C13H13NO6 [M]+ 279.0743; found
279.0765. Selected data for the minor diastereomer (2S*,3a-
S*,6aR*)-5g: tR = 20.14 min. 1H NMR (400 MHz, CDCl3): δ =
5.82 (d, J = 4.9 Hz, 1 H, OCHO), 5.50 (dd, J = 9.2, 6.2 Hz, 1 H,
OCHAr) ppm. MS (EI): m/z (%) = 262 (5) [M – OH]+, 217 (10),
216 (23), 206 (10), 191 (11), 190 (11), 188 (11), 187 (11), 178 (11),
177 (10), 176 (19), 174 (12), 165 (11), 149 (15), 148 (17), 136 (20),
135 (23), 121 (10), 120 (18), 115 (12), 89 (11), 84 (31), 83 (100), 77
(15), 70 (11), 69 (18), 65 (13), 63 (18), 62 (15), 56 (15), 55 (37), 54
(10), 53 (14), 51 (10).
(CH CHCH ), 14.1 (CH CH O) ppm. IR (film): ν = 1745, 1244,
˜
2
2
3
2
1177 cm–1. MS (EI): m/z (%) = 254 (Ͻ1%) [M]+, 182 (8), 181 (100),
164 (5), 135 (7), 115 (10), 83 (5), 69 (7), 55 (7). HRMS (EI): calcd.
for C10H13O4F3 [M]+ 254.0766; found 254.0767. Selected data for
the minor diastereomer (2R*,3aS*,6aR*)-5d: tR = 10.74 min. 1H
NMR (400 MHz, CDCl3): δ = 6.02 (d, J = 4.9 Hz, 1 H,
OCHO) ppm. MS (EI): m/z (%) = 254 (Ͻ1%) [M]+, 182 (7), 181
(100), 135 (6), 115 (8), 69 (5).
(3aS*,6aR*)-Diethyl
Perhydrofuro[2,3-b]furan-2,2-dicarboxylate
(5e): Colorless oil; Rf = 0.48 (hexane/EtOAc, 8:2); tR = 14.68 min.
1H NMR (400 MHz, CDCl3): δ = 5.97 (d, J = 5.2 Hz, 1 H, OCHO),
4.38–4.14 (m, 4 H, 2 OCH2CH3), 4.02–3.83 (m, 2 H, OCH2CH2),
3.07–2.88 (m, 1 H, CH2CHCH2), 2.60 (dd, J = 13.8, 9.6 Hz, 1 H,
CHHC), 2.42 (dd, J = 13.8, 6.6 Hz, 1 H, CHHC), 2.02 (ddt, J =
12.6, 10.8, 8.3 Hz, 1 H, CHHCH2O), 1.77 (ddt, J = 12.6, 5.4,
1.6 Hz, 1 H, CHHCH2O), 1.28 (t, J = 7.1 Hz, 3 H, CH3CH2O),
1.26 (t, J = 7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.8, 168.4 (2 CO2), 111.7 (OCHO), 87.2 (CCO2),
67.1 (OCH2CH2), 62.3, 62.2 (2 CH2CH3), 42.3 (CH2CHCH2), 37.6,
Acknowledgments
This work was generously supported by the Spanish Ministerio de
Ciencia e Innovación (MICINN), grant number CTQ2007-65218
and Consolider Ingenio 2010, grant number CSD2007-00006, the
Generalitat Valenciana (GV; PROMETEO/2009/039), and Fondos
Europeos para el Desarrollo Regional (FEDER). D. S. thanks the
Vicerrectorado de Investigación, Desarrollo e Innovación of the
Universidad de Alicante for a predoctoral grant. M. R.-F. thanks
the ISO of the Universidad de Alicante for a postdoctoral grant.
32.2 (CH CHCH ), 14.2, 14.1 (2 CH CH ) ppm. IR (film): ν =
˜
2
2
3
2
1742, 1283, 1238, 1118, 1064, 1027 cm–1. MS (EI): m/z (%) = 258
(Ͻ1%) [M]+, 186 (11), 185 (100), 139 (11), 129 (12), 111 (15), 83
(44), 55 (12). HRMS (EI): calcd. for C12H18O6 [M]+ 258.1103;
found 258.1073.
(2R*,3aS*,6aR*)-2-(Pentafluorophenyl)perhydrofuro[2,3-b]furan
(5f): Colorless oil; Rf = 0.62 (hexane/EtOAc, 1:1); tR = 13.33 min.
1H NMR (400 MHz, CDCl3): δ = 5.91 (d, J = 4.9 Hz, 1 H, OCHO),
5.47 (dd, J = 9.5, 6.9 Hz, 1 H, OCHAr), 4.09–3.95 (m, 2 H,
OCH2CH2), 3.19–3.09 (m, 1 H, CH2CHCH2), 2.48–2.33, 2.27–
2.11, 1.88–1.79 (3 m, 4 H, CH2 CHCH2) ppm. 13 C NMR
[1] For some recent examples, see: a) X.-C. Huang, S. Qin, Y.-W.
Guo, K. Krohn, Helv. Chim. Acta 2008, 91, 628–634; b) X.-F.
Wu, Y.-C. Hu, S.-S. Yu, N. Jiang, J. Ma, R.-X. Tan, Y. Li, H.-
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1
(100 MHz, CDCl3): δ = 145.4 (d, JC,F = 253.6 Hz, ArCF), 141.1
1
1
(d, JC,F = 260.7 Hz, ArCF), 137.8 (d, JC,F = 254.0 Hz, ArCF),
114.8 (ArC), 110.0 (OCHO), 71.6 (OCHAr), 68.2 (OCH2CH2),
43.3 (CH CHCH ), 38.4, 32.5 (CH CHCH ) ppm. IR (film): ν =
˜
2
2
2
2
1737, 1655, 1524, 1506, 1132, 1020 cm–1. MS (EI): m/z (%) = 280
6468
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6459–6469

Synthesis of Perhydrofuro[2,3-b]furans from Isopentenyl Alcohol
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Received: July 1, 2011
Published Online: September 21, 2011
Eur. J. Org. Chem. 2011, 6459–6469
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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