New methodology for the synthesis of tetrahydrofuro[3,2-b]furan-2(3H)-one derivatives, synthons of natural products with biological interest

Article abstract of DOI:10.1016/j.tet.2016.09.004

A new methodology is presented to synthesize in a regio and stereoselective manner tetrahydrofuro[3,2-b]furan-2(3H)-one, structural subunit present in a wide variety of natural products present in plant, fungi, algae, insects, and other living organisms.

Full text of DOI:10.1016/j.tet.2016.09.004

Accepted Manuscript
New methodology for the synthesis of tetrahydrofuro[3,2-b]furan-2(3H)-one
derivatives, synthons of natural products with biological interest
Ángel M. Montaña, Joan A. Barcia, Pedro M. Grima, Gabriele Kociok-Köhn
PII:
S0040-4020(16)30897-3
10.1016/j.tet.2016.09.004
TET 28075
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 July 2016
Revised Date: 2 September 2016
Accepted Date: 5 September 2016
Please cite this article as: Montaña EM, Barcia JA, Grima PM, Kociok-Köhn G, New methodology for
the synthesis of tetrahydrofuro[3,2-b]furan-2(3H)-one derivatives, synthons of natural products with
biological interest, Tetrahedron (2016), doi: 10.1016/j.tet.2016.09.004.
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ACCEPTED MANUSCRIPT
GRAPHICAL ABSTRACT
New methodology for the synthesis of tetrahydrofuro[3,2-b]furan-2(3H)-one derivatives,
synthons of natural products with biological interest
Ángel M. Montaña*, Joan A. Barcia, Pedro M. Grima and Gabriele Kociok-Köhn

ACCEPTED MANUSCRIPT
New methodology for the synthesis of tetrahydrofuro[3,2-b]furan-
2
(3H)-one derivatives, synthons of natural products with biological
interest
a
a
a
b
Ángel M. Montaña *, Joan A. Barcia , Pedro M. Grima and Gabriele Kociok-Köhn
a
Industrial and Applied Organic Chemistry Research Unit, Department of Organic and
Inorganic Chemistry, University of Barcelona, c/ Martí Franquès 1-11, 08028-
Barcelona, Spain.
b
Department of Chemistry, University of Bath,Bath, BA2 7AY, UK
*
To whom correspondence should be addressed.
ABSTRACT:
A new methodology is presented to synthesize in a regio and stereoselective manner
tetrahydrofuro[3,2-b]furan-2(3H)-one, structural subunit present in a wide variety of
natural products present in plant, fungi, algae , insects and other living organisms. This
secondary metabolites have important biological properties and have shown to be very
active in different therapeutic areas. This method consists in the reaction of highly
substituted 2-oxyallyl cations, generated in situ from the corresponding dihaloketone,
and 2-functionalized furans (in our case 2-NHBoc-furan). It is a one-pot reaction that
affords the desired furofuranones with high regio- and stereoselectivity. The new
synthetic method is simple, straightforward and versatile, because a wide variety of
furofuranones, and with wide molecular diversity, may be prepared by adequately
designing the substituents of starting materials. The resulting furofuranones may be
potentially derivatized to generate chemical libraries of high molecular diversity, which
are very useful when developing structure-activity relationship studies.
Keywords: furan, oxyallyl cation, tetrahydrofuro[3,2-b]furan-2(3H)-one, 2,6-
dioxabicyclo[3.3.0]octan-3-one, γ-lactones, haloketones, 2-functionalized furans, [3+2]-
cycloaddition, [4+3]-cycloaddition.
1
. Introduction
-
1 -

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The tetrahydrofuro[3,2-b]furan-2(3H)-one structural subunit is present in natural
products from many different living organisms: superior plants, fungi, algae, sponges,
insects, etc. Some of these compounds like goniofufurone and analogues are active as
1
cytotoxic agents against lymphocytic leukaemia and human lung carcinoma (Figure 1).
Secondary metabolites from Caribbean sponges like plakortones A-F constitute a
2
+
new class of activators of cardiac SR-Ca -pumping ATPase, and are relevant to
correction of cardiac relaxation irregularities. Other plakortones exhibit in vitro
cytotoxic activity on a murine fibrosarcoma cell line, so that overall, the plakortones
2
represent a new family of natural products of substantial pharmacological interest. On
the other hand, the nortriterpenoids rubriflordilactones from Schisandra rubriflora
(Figure 1) are a class of structurally and biologically attractive compounds due to their
3
promising anti-HIV activity.
In addition, their attractive architectures represent a formidable synthetic
challenge. Furthermore diachasmimorpholides secreted by abdominal glands of
braconid wasps, Diachasmimorpha longicaudata and Diachasmimorpha tryoni are
important fragrant volatile biological control agents acting as semiochemicals with great
4
ecological interest. It is also worth noting the interest of furofuranones derived from D-
5
aldoses, as analogues of goniofufurone, with interesting cytotoxic activity.
-
2 -

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Goniofufurone:
Rubriflordilactone A
(Schisandra rubriflora)
Schisandraceae
Rubriflordilactone B
R = H, R = OH, R = H,
1
2
3
R = OH
4
7
-epi-Goniofufurone:
R = OH, R = H, R = H,
1
2
3
R = OH
4
(
Goniothalamus giganteus)
Annonaceae
Plakortone A R' = Et
Plakortone B R' = Me
Diachasmimorpholides
R = n-C H , R = H
1
4
9
2
Plakortis halichondrioides
R = n-C H , R = H
1 6 13 2
and Plakortis simplex
R = H, R = n-C H
1 2 4
9
(
Caribbean sponges)
R = H, R = n-C H
1 2 6
13
Diachasmimorpha longicaudata
and Diachasmimorpha tryoni
(
Hymenoptera Braconidae, wasp parasitoid)
cis-D-Glucofurofuranone
cis-D-Xylofurofuranone
cis-D-Ribofurofuranone
Figure 1. Examples of natural products, having the substructure tetrahydrofuro[3,2-b]furan-2(3H)-one,
with interesting biological activities.
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3 -

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The structural subunit cis-2,6-dioxabicyclo[3.3.0]octane or perhydrofuro[3,2-
b]furan is even more widely present in Nature than its furofuranone analogue. Thus,
6
natural products like mycotoxin erythroskyrine from (Penicillium islandicum),
7
Laurenenines A and B from algae (Laurentia nipponica) are good examples. On the
other hand, synthetic products like isosorbide (starting material for synthesis of
8
biobased polymers and also for pharmaceutical applications), isosorbide dinitrate
9
(
vasodilator of use in cardiac therapy for angina pectoris, congestive heart failure,
1
0
esophageal spasms and also to treat glaucoma ) or even 3-(trialkylammonium)-
1
1
isosorbide derived salts (used as catalysts in asymmetric synthesis) are also good
examples of the versatility of this structural difuran framework.
For the aforementioned important properties, tetrahydrofuro[3,2-b]furan-2(3H)-
ones have been a synthetic target since long time ago and several methodologies have
1
, 12,13,14,15,16
been developed for this purpose.
Based in our previous experience in the reactivity of oxyallyl cations, [4+3]-
1
7
cycloaddition reactions and related methodologies, we present here a new synthetic
method, which is simple, straightforward and versatile, because a wide variety of
furofuranones, and with wide molecular diversity, may be prepared by adequately
designing the substituents of starting materials. This method consists in the reaction of
highly substituted 2-oxyallyl cations, generated in situ from the corresponding
dihaloketone II, and 2-functionalized furans I (in our case 2-NHBoc-furan) (Figure 2)
to afford alkylidene-furofuranones III, which can be transformed into a wide variety of
derivatives (ie. IV, V or VI) by straightforward reactions. The key reaction leading to
III is a [3+2] cycloaddition that takes place by a one-pot process and with high regio-
and stereoselectivity.
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4 -

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Figure 2. New methodology to prepare furofuranones and potential derivatives.
2
. Results and discussion
2
.1. Preparation of substrates: synthesis of dibromoketones 1 and 3 and 2-(tert-
butoxycarbonylamino)-furan, 6
To simplify the reaction outcome in this particular study we have used
symmetric dihaloketones 1 and 3. This methodology may be applied to other
tetrasubstituted dissymmetric dihaloketones II (R ≠R ≠R ≠R ) (Figure 2); but, a
1
2
3
4
mixture of diastereoisomeric products will be formed; however, a certain degree of
stereoselectivity may be expected. In any case, as it will be discussed latter on, it is of
great importance that the ketone should be α,α,α’,α’-tetrasubstituted and with steric
demanding substituents in order to get good yields of furofuranones. Dibromoketones 1
and 3 were easily obtained by bromination of the corresponding commercially available
1
8
ketones, following well described procedures. The results from the synthesis of
dibromoketones are quoted in Table 1.
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5 -

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Table 1. Reaction outcome of bromination of precursor ketones to obtain 1 and 3.
b
c
Product
Yield
%)
a
Entry
Precursor
(
O
Br
Br
8
1
4
0
O
1
1
2
O
O
2
3
74
Br
Br
3
4
d
79
(
(
(
a) Reaction conditions: substrate/Br 1:2, catalytic amount of PBr , 0ºC, 2 h.
2 3
b) Isolable by vacuum fractional distillation. (c) Yield on isolated product.
d) Meso/dl ratio 4:1.
The synthesis of products 1 and 3 and in general of all tetrasubstituted ketones does
not present special problems due to there are only two active positions to be
halogenated. The yield in both cases was good and in the case of diisopropyl ketone
only a 10% of monobrominated product 2 was formed. This byproduct was efficiently
separated by vacuum fractional distillation.
The other substrate used for this methodology was the tert-butyl N-(2-furoyl)-
carbamate 6. It is of capital importance for the obtention of desired
alkylidenefurofuranones that the furan ring should be functionalized on C2. Moreover,
this function should exert also a certain degree of steric hindrance. In this particular
work we have selected the carbamate function bur other functions like for example
(
CH ) C-COO‒, among other, may be used.
3 3
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6 -

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The non-commercial 2-(NHBoc)-furan 6 was obtained following the procedure
1
9
described by Lynch et al. This procedure involves a one-pot reaction between the 2-
furoyl chloride, sodium azide and an excess of tert-butyl alcohol. The reaction takes
place by a Curtius rearrangement of the intermediate 2-furoyl azide to obtain, in 82%
yield, the desired 2-aminofuran 6. (Figure 3). Even the reaction may be carried out by a
one-pot process, the intermediate acylazide 5 may be isolated. However, due to its
instability it is recommended to carry out the reaction at once.
Figure 3. Formation of the tert-butyl N-(2-furoyl)-carbamate.
2
.2. Generation of oxyallyl cation and its cycloaddition to C2-functionalized furan
The coupling between the dihaloketones and C2-functionalized furan takes place via
a [3+2] cycloaddition reaction, where the reactive intermediates are the zwitterionic
oxyallyl cations (Figure 4), which act, in first instance, as electrophiles. These oxyallyl
cations are generated in situ by reaction of dihaloketones with reducing metals: Cu, Zn,
Zn/Cu pair, Ag, Fe (CO) , etc. Nevertheless, their electrophilicity is minored by the
2
9
positive inductive effects exerted by alkyl substituents, but could be increased by
choosing the adequate counterion for the oxide moiety. Thus, metallic counterions that
form more covalent bonds with the oxygen atom of oxyallyl cation are more
2
0
electrophilic, i.e.: O─Fe > O─Zn > O─Cu. In this particular work, we have used as
reducing metal the pair Zn/Cu.
+
Figure 4. Oxyallyl cations generated in situ from dibromoketones 1 and 3. Counterion M comes
from the reducing metal used in the reaction.
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7 -

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Table 2. Results from the cycloaddition reaction between the oxyallyl cation generated in situ from
dihaloketones of different steric hindrance and 2-(NHBoc)-furan and/or regular furan.
Metal
Entry
Furan
Haloketone
T(ºC) tr(h)
[3+2]-Cycloadduct
[4+3]-Cycloadduct
(
Solvent)
a
Yield (%)
O
Zn/Cu
1
0
1.5
Br
Br
(
ACN)
6
6
1
8
(4%)
7
(56%)
O
Zn/Cu
(ACN)
2
0 to rt
5
Br
Br
3
9 (73%)
11 (0%)
11 (0%)
10 (0%)
Zn/Cu
‒10
3
4
5
(
ACN)
to rt
6
6
b
4
12 (33%)
Fe (CO)
‒10
2
9
6.5
(
ACN)
to rt
c
4
12 (76%)
O
Zn/Cu
5
6
rt
4.5
1.5
Br
Br
(
ACN)
1
1
4(57%)
1
3 (0%)
5 (0%)
d
O
Zn/Cu
(ACN/
‒44
Br
Br
3
CH Cl 1:1)
2 2
16 (64%)
1
(
a) Yield on isolated product. (b) Mixture of diastereoisomers: trans / cis-diequatorial / cis-diaxial:
21
20
3
8/55/7. (c) Mixture of diastereoisomers: trans / cis-diequatorial / cis-diaxial: 55/40/5. (d) Me SiCl
3
(
1:1 molar ratio respect to dihaloketone) was added to activate the metallic particles and to form silyl
2
2
derivatives of oxyallyl cation.
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8 -

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The formation of furofuranones 7 and 9 takes place by a [3C(2π)+2C(2π)]
stepwise cycloaddition (Figure 5), via the electrophilic attack of the oxyallyl cation to
the C5 position of 2-(NHBoc)-furan in a regioselective manner, as will be commented
latter on. The generated intermediate I undergoes an intramolecular nucleophilic attack
of the O-enolate to the allyl cation, also in a regioselective way, affording intermediates
III/IV, which result hydrolyzed during the reaction work-up, forming the final product
7
. A small amount (5%) of alcohol 17 was isolated from the reaction crude, which we
believe is a byproduct generated within the column chromatography during the
purification process, as a result of addition of residual water (present in solvents) to the
C=C double bond, catalyzed by the SiO matrix. Simultaneously to the formation of
2
furofuranone 7 a small amount (4%) of [4+3]-cycloadduct 8 was formed. For less
substituted dihaloketones (i.e. 2,4-dibromo-3-pentanone) used as precursors of much
less hindered oxyallyl cations, the [4C(4π)+2C(2π)]-cycloadduct 12 (as a mixture of
three diastereoisomers) is the only product (see entries 3 and 4 in Table 2) not
observing, at all, the formation of furofuranones 11. For these particular substrates the
yield of [4+3]-cycloadducts increases from 33% up to 76%, when using Fe (CO)
2
9
instead of Cu/Zn as reducing agent. On the other hand, when increasing the steric
hindrance of oxyallyl cation (3’), generated from haloketone 3, the yield of the
corresponding furofuranone 9 increased up to 73% and no [4+3]-cycloadduct 10 was
formed (entry 2, Table 2). Therefore, the steric hindrance of the oxyallyl cation is a
required structural condition to generate the desired furofuranones. Finally, when
reacting hindered dihaloketones 1 and 3, with regular furan (entries 5 and 6 from Table
2
), without the C2-functionalization, only [4+3]-cycloadducts 14 and 16 are formed,
respectively; but no traces of the corresponding furofurans 13 or 15 are detected. Thus,
it is of capital importance that the furan diene should be functionalized at C2 to
undergo a [3+2]-cycloaddition instead of a [4+3]-cycloaddition.
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9 -

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Figure 5. Mechanism proposal for the formation of products 7, 8 and 17.
2
.3. Regioselectivity in the formation of [3+2]-cycloadducts 7 and 9
Analyzing the results from entries 1 and 2 of Table 2, it is worth noting the
regioselectivity observed in the formation of [3+2]-cycloadducts 7 and 9. This
regioselectivity takes place at two levels: a) In the initial attack of the oxyallyl cation 1
to the C5 position of 2-(NHBoc)-furan to generate intermediate I; and b) In the attack of
enolate (O-enolate) to the C4 position of intermediate I to generate intermediate II (see
Figure 5). In both cases, the driving force it is not thermodynamic, in other words it is
not dependent on the difference of stability between the [4+3]-cycloadduct 8 (ꢀH = ‒
f
1
87.07 kcal/mol) and the [3+2]-cycloadduct II (ꢀH = ‒183.83 kcal/mol) (See Table
f
S1). On the other hand, the initial regioselectivity (a) is consistent with the different
electron density, electron charge and potential values at positions C2 or C5 of furan
substrate 6, which is favorable for the attack to C5 position by the oxyallyl cation 1’.
This C5 position has higher electron density than C2, according to the calculation of
electron charges by natural population analysis (NPA) and the electrostatic potential
-
10 -

ACCEPTED MANUSCRIPT
map (ESPM) (see Table S2). Also the different possibilities of cyclization of
intermediate I have been evaluated: attack of C-enolate versus O-enolate and attack on
C2 or on C4 ring positions. These possibilities have been studied taking into account the
energy balance and the charge distribution among the different intermediates and we
have concluded that none of them are responsible for the regioselectivity experimentally
observed. The regioselectivity observed at this level (b) and also at initial level (a) are
both mainly due to the maximum overlap of frontier molecular orbitals (FMO): HOMO
from 6 and LUMO from 1’ in the initial electrophilic attack to the furan diene (see
Figure S1 and Figure S2), and HOMO of O-enolate and LUMO of allyl cation subunit
in the case of intramolecular cyclization of intermediate I to afford II (see Figure S3
and Table S3). In both cases there is a narrow HOMO-LUMO energy gap. These
parameters have been calculated by Gaussian at the theory level and basis set:
DFT/B3LYP/6-31G++(d,p). The founding of regioselectivity on the basis of FMO for
2
3
the case of cycloadditions have many precedents in the literature.
There are other factors facilitating the easy attack of O-enolate to the C4 position
of intermediate I. In first place, the availability of a minimum energy conformation that
allows the approach of both reactive sites, putting apart the steric demanding
isopropylidene subunit and the tert-butoxy group. The approach is also facilitated by the
2
4
Thorpe-Ingold effect exerted by the gem-dimethyl group of the side chain that forces
the approach of the afore-mentioned reaction sites (see Figure 6).
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11 -

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Figure 6. Minimum energy conformation for intermediate I. Effects facilitating the approach of
the reactive sites.
2
1
.4. Structural determination of cycloaddition products
All products, both [4+3]- and [3+2]-cycloadducts, as well as the addition product
7 were isolated, purified and physically and spectroscopically characterized. The
1
13
determination of relative stereochemistry was established by H- and C-NMR
2
5
1
13
correlation after a careful analysis and signal assignment of their 1D ( H and C) and
D NMR spectra (COSY, HSQC and NOESY). The structure of the new furofuranones
2
was confirmed for the case of 17 by X-ray diffraction analysis of a single crystal. The
ellipsoid diagram and unit cell packing for this structure are illustrated in Figure 7 and
the refinement data are quoted in Table 3.
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12 -

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Figure 7. A) On the top: X-ray structure of 17. Ellipsoid diagram drawn at the 50% probability level for
1
2, showing the atom-labeling scheme. The numbering assigned by the X-ray data processing software is
not IUPAC numbering. B) On the bottom. Crystal packing of 17. Unit cell. Hydrogen bonds are observed
between the hydroxyl groups (donors) and the carbonylic oxygen (acceptor) of the neighbor molecule in
the unit cell.
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13 -

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Table 3. Crystal data and structure refinement for 17.
Empirical formula
Formula weight
Temperature
C H O
11 18 4
214.25
150(2) K
Wavelength
0.71073 Å
Crystal system
Space group
Triclinic
P  1
Unit cell dimensions
a = 5.9190(2) Å α = 80.919(2) deg.
b = 7.5470(3) Å β = 85.315(2) deg.
c = 12.6220(5) Å γ = 81.231(2) deg.
3
Volume
549.30(4) Å
Z
2
3
Calculated density
Absorption coefficient
F(000)
1.295 Mg/m
-1
0.097 mm
232
Crystal size
0.60 x 0.50 x 0.50 mm
3.49 to 30.55 deg.
Theta range for data collection
Limiting indices
‒8 ≤ h ≤ 8, ‒10 ≤ k ≤ 10, ‒17 ≤ l ≤ 18
9695 / 3188 [R(int) = 0.0741]
94.5 %
Reflections collected / unique
Completeness to θ = 30.55
Max. and min. transmission
Refinement method
Data / restraints / parameters
0.9529 and 0.9438
2
Full-matrix least-squares on F
3188 / 0 / 142
2
Goodness-of-fit on F
1.051
Final R indices [I > 2σ(I)]
R indices (all data)
R1 = 0.0592, wR2 = 0.1594
R1 = 0.0642, wR2 = 0.1640
-3
Largest diff. peak and hole
0.437 and -0.274 e.Å
3
. Conclusions
In the present work, we describe a new methodology to generate furofuranones,
which are key building blocks in many natural products with biological interest. The
formation of furofuranones takes place by a [3C(2π)+2C(2π)] stepwise cycloaddition,
via the electrophilic attack of the oxyallyl cation to the C5 position of 2-(NHBoc)-furan
in a regioselective manner. The generated intermediate undergoes an intramolecular
-
14 -

ACCEPTED MANUSCRIPT
nucleophilic attack of the O-enolate to the cyclic allyl cation, also in a regioselective
way, affording an enamine intermediate that results hydrolyzed during the reaction
work-up, forming the final product. This regioselectivity would be controlled by frontier
MOs of cycloaddends. Thus, the more stable regioisomeric transition states arise
through interaction of the reaction sites with the in-phase orbitals having the larger MO
coefficients. It is important to mention that steric hindrance of the oxyallyl cation is a
required structural condition to generate the desired furofuranones. Also, it is of capital
importance that the furan diene should be functionalized at C2 to undergo a [3+2]-
cycloaddition instead of a [4+3]-cycloaddition. These alkylidene-furofuranones may be
potentially transformed into added-value derivatives by conventional ozonolysis,
hydrogenation or addition reactions. All products have been isolated, purified and
physically and spectroscopically characterized. Extension of this methodology to other
synthetic objectives is under way in our laboratory.
4
. Author information
Corresponding author
Phone: +34-934.021.681. Fax: +34-933.397.878. E-mail: angel.montana@ub.edu
Notes
The authors declare neither competing financial interest nor any other conflict of
interest.
5
. Acknowledgements
We thank the Spanish Ministry of Economics and Competitiveness (MINECO) for
financial support (Grant: CTQ2015-65040-P). In addition, financial support from the
University of Barcelona (Grant: UB-VRR-2012/AR000126) and from the Generalitat de
Catalunya (Grant: AGAUR 2014-SGR-1658), is also gratefully acknowledged.
6
. Experimental section
6
.1. General procedures
NMR spectra were recorded on a Varian Inova 200 or 300 MHz, on a Varian Mercury
00 MHz and/or in a Bruker DMX 500 MHz apparatus. Chemical shifts (δ) are
expressed in ppm versus tetramethylsilane as an internal standard. IR spectra were
4
-
15 -

ACCEPTED MANUSCRIPT
recorded on a NICOLET 6700 FT-IR by film, KBr pellet or ATR (Attenuated Total
Reflectance) methods. Mass spectrometry was performed on a Hewlett-Packard 5890
apparatus, generally under a CI (Chemical Ionization) method by using NH or CH or
3
4
by direct insertion under Electron Impact at 70 eV and 150 ºC. The elemental analyses
were obtained in a FISONS Elemental Analyzer, Model Na-1500. The samples were
previously pyrolized al 1000 ºC in the presence of a catalyst, under oxygen atmosphere,
and the content of carbon, hydrogen and nitrogen were determined by evaluation of the
combustion gases by gas chromatography using a FID detector. Solvents were dried,
according to standard procedures, and distilled prior to use. All other major chemicals
were obtained from commercial sources and used without further purification. Gas
chromatography was performed by using a Shimatzu AOC-20i apparatus with a
capillary column (HP-5 Crosslinked 5% Phe-Me-Siloxane, 0.25 ꢁm film thickness, 30
m length and 0.32 mm diameter). Used carrier gas brands and pressures were: He = 5.5
bar (Linde, Helium 5.0), Air = 3 bar (Linde, synthetic air), H = 3 bar (Linde, Hydrogen
2
5
.0). The experimental conditions are specified in each case. Ozonolysis reaction was
carried out using an ozone-generator Fischer Ozone-500 apparatus, under the following
conditions: Intensity = 0.25-0.40 A, P = 0.25 bar, O flow = 50-100 mL/min.
O2
3
6
.2. Molecular computer calculations
Geometry and energy minimization of molecules were preoptimized by molecular
mechanics MM2 followed by semiempirical quantum mechanical PM7 algorithm,
2
6
27
implemented in the MOPAC-2016 software (Ver. 16.146W). This software was also
used to calculate the formation enthalpy and total energy of molecules. Density
2
8,29
functional theory (DFT) based methods at the B3LYP functional level
were used for
subsequent full refinements, within the Gaussian-03W (Revision E.01, version 6.1)
3
0
31
software package and using the 6–31++G(d, p) basis set. All calculations were
performed on isolated molecules (gas phase). The atomic charges were calculated on the
basis of both Mulliken population analysis and natural population analysis (NPA), being
the last one more adequate for the present study.
6
.3. X-ray Crystal Structure Analysis of 17
Pure cycloadduct 17 was dissolved in a minimum amount of ethyl acetate at room
temperature. A few drops of hexane were added and the saturated solution kept in a
refrigerator at 4 °C. Suitable single crystals for X-ray diffraction studies grew over a
-
16 -

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period of 1 week. A single crystal (0.60 x 0.50 x 0.50 mm) of 17 was mounted on a
Nonius–Kappa CCD diffractometer, equipped with an Oxford Cryosystem, using
graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). Intensity data were
3
2
collected at 150 K and the data were processed by using the Nonius software.
A
symmetry-related (multiscan) absorption correction was applied. 9695 reflections were
measured in the range 3.49 ≤ θ ≤ 30.55 deg. 3188 reflections were assumed as observed
applying the condition I > 2σ(I). The structures were solved by direct methods (SIR-
3
3
34
9
7) and refined by full-matrix least-squares techniques against F2 (SHELXL-2013)
3
5
using the program platform SHELXle. Non-hydrogen atoms were anisotropically
refined. Heteroatom and hydrogen atoms were located in the difference Fourier map and
were isotropically refined all others were placed onto calculated positions. The final
2
R(on F) factors were: 0.0592, wR(on |F| ) = 0.1594 and goodness of fit = 1.051 for all
observed reflections. The number of refined parameters was 142 and the maximum and
-3
minimum peaks in final difference synthesis was 0.437 and ‒0.274 e.Å . The crystal
data and a summary of the intensity data collection for 17 are summarized in Table 3.
Data for crystal and structure refinements, atomic coordinates, bond lengths, bond
angles, anisotropic displacement parameters, and hydrogen coordinates may be obtained
from the CIF file deposited with The Cambridge Crystallographic Data Centre with the
number CCDC-1487367. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
the
Internet
at
www.ccdc.cam.ac.uk/data_request/cif. The molecular illustrations such as the thermal
ellipsoid plot and the unit cell packing (Figures 7A and 7B) were made by using
3
6
37
ORTEP-III and MERCURY 3.8 software, respectively.
6
.4. Synthetic procedures
6
.4.1. Synthesis of 2,4-dibromo-2,4-dimethyl-3-pentanone, (1). Isolation and
characterization of minor product 2-bromo-2,4-dimethyl-3-pentanone (2)
-
17 -

ACCEPTED MANUSCRIPT
In an oven-dried 100 mL three neck round-bottom flask, equipped with a stirring bar, a
Dimroth condenser, a calcium chloride trap, a thermometer and a pressure equalized
addition funnel, 2,4-dimethyl-3-pentanone (24.2 mL, 19.50 g, 171 mmol) and
phosphorous tribromide (0.4 mL, 1.43 g, 5.27 mmol) were added. The mixture was
cooled to 0 ºC and bromide (18.0 mL, 56.14 g, 351 mmol), was slowly added along 5
hours, maintaining the reaction mixture between 5 ºC and 10 ºC. During the addition of
bromine, the formation of hydrogen bromide was observed. One hour after the complete
addition of bromine, the conversion of 2,4-dimethyl-3-pentanone was complete as
observed by GC. Then, the mixture was submitted to vacuum (20 mmHg) for 30 min at
rt to eliminate the dissolved hydrogen bromide. The reaction crude was purified by
fractional distillation under vacuum (10 mmHg), collecting the fraction between 85 ºC
and 90 ºC. This fraction was redistilled to obtain chemically pure 2,4-dibromo-2,4-
dimethy-pentan-3-one (1) (39.1 g, 84% yield) as a colourless oil, which freezes at ‒24
ºC. This product should be stored in the dark and at low temperature to avoid
decomposition.
-1 1
IR (film): ῡ = 2979, 2934, 1697 (C=O, st), 1462, 1387, 1373, 1109, 1040, 993 cm . H
1
3
NMR (200 MHz, CDCl ): δ = 2.15 (12H, s, H1, H5, H6 and H7) ppm. C NMR (50
3
MHz, CDCl ): δ = 32.7 (C1, C5, C6 and C7), 61.5 (C2 and C4), 188.1 (C3) ppm. MS
3
[
GC-MS(CI), NH , 70 eV, 150 ºC]: m/z (%) = 265 (16, M+N H ), 248 (100, M+NH ),
3 2 7 4
2
1
90 (100, M+NH ), 272 (1, M). GC (50 ºC, 1 min, 10 ºC/min., 250 ºC, 1 min): t =
4 R
1.52 min.
The fraction distilled at 70-80 ºC and 10 mmHg, from the reaction crude, consists of 2-
bromo-2,4-dimethyl-3-pentanone (2) (3.8 g, 10% yield)
-1
1
IR (film): ῡ = 2980, 2930, 1702 (C=O, st), 1458, 1390, 1381, 1109 cm . H NMR (200
MHz, CDCl ): δ = 1.17 (6H, d, J = 7.2 Hz, H5 and H7), 1.87 (6H, s, H1 and H6), 3.45
3
(
1H, q, J = 7.2 Hz, H4). GC (50 ºC, 1 min, 10 ºC/min., 250 ºC, 1 min): t = 7.54 min.
R
-
18 -

ACCEPTED MANUSCRIPT
6
.4.2. Synthesis of 1',1"-dibromo-dicyclohexylketone, (3).
Dihaloketone 3 was prepared following a procedure similar to the previously described,
buy using dicyclohexylketone (10.0 g, 51.5 mmol) as a starting material and
phosphorous tribromide (0.2 mL, 0.57 g, 2.1 mmol). The mixture was cooled to 0 ºC
and bromine (5.2 mL, 16.21 g, 101 mmol) was added along 2 h, maintaining the
reaction mixture between 5 ºC and 10 ºC. During the addition of bromine, the formation
of hydrogen bromide was observed. After completion, the reaction mixture was
submitted to vacuum (20 mmHg) for 30 min at rt to eliminate the dissolved hydrogen
bromide. The crude mixture became solid at rt and it was dissolved in CH Cl and
2
2
washed with cold aqueous 10% Na S O solution (25 mL) and ice-water (2 x 25 mL).
2
2
3
The organic phase was dried over anhydrous MgSO , filtered and concentrated to
4
dryness, affording dihaloketone 3 as a white solid (13.4 g, 74% yield). This solid should
be stored in the dark and at low temperature to avoid decomposition.
-1
IR (film): ῡ = 2934, 2857, 1703 (C=O, st), 1447, 1277, 1242, 1155, 1115, 1032 cm .
1
H NMR (200 MHz, CDCl ): δ = 1.30-1.79 (20H, m, H2', H3', H4', H5', H6', H2'', H3'',
3
1
3
H4'', H5'' and H6'') ppm. C NMR (50 MHz, CDCl ): δ = 22.8 (C4' and C4''), 24.9
3
(C3', C3'', C5' and C5''), 38.1 (C2', C2'', C6' and C6''), 72.1 (C1' and C1''), 196.6 (C1).
MS [GC-MS(CI), NH , 70 eV, 150 ºC]: m/z (%) = 369 (69, M+NH ), 292 (100, M-
3
3
Br+NH3).
6
.4.3. Synthesis of 2,4-dibromopentan-3-one, (4)
-
19 -

ACCEPTED MANUSCRIPT
In an oven-dried 250 mL three neck round-bottom flask, equipped with a stirring bar, a
Dimroth condenser, a calcium chloride trap, a thermometer and a pressure equalized
addition funnel, 3-pentanone (27 mL, 22g, 0.255 mol) and phosphorous tribromide (0.5
mL, 1.43g, 5.3 mmol) were added. The mixture was cooled to 0 ºC and bromide (27
mL, 84.2g, 0.527 mol) was slowly added along 5 hours, maintaining the reaction
mixture between 5 ºC and 10 ºC. During the addition of bromine, the formation of
hydrogen bromide was observed. One hour after the complete addition of bromine, the
conversion of 3-pentanone was complete as observed by GC. Then, the mixture was
submitted to vacuum (20 torr) for 30 min at rt to eliminate the dissolved hydrogen
bromide. The reaction crude was purified by fractional distillation under vacuum (10
mmHg), collecting the fraction between 65 ºC and 70 ºC. This fraction was redistilled to
obtain chemically pure 2,4-dibromopentan-3-one 4 (49.15 g, 79% yield) as a colourless
oily diastereoisomeric mixture: meso / dl pair 4/1.
3
IR (film) ῡ = 3445 (C=O), 2980, 2920, 2875 (H─Csp ), 1730 (C=O), 1440, 1380, 1350
-1 1
(
C─C, C─H), 1200, 1120, 1070, 1050, 1020 (C─O) cm . H NMR (200 MHz, CDCl )
3
pair dl: δ = 1.88 (2H, d, J = 6.9 Hz, H2, H4), 4.77 (6H, q, J = 6.9 Hz, H1, H5); meso: δ
1
3
=
1.81 (2H, d, J = 6.7 Hz, H2, H4), 4.99 (6H, q, J = 6.7 Hz, H1, H5) ppm. C NMR
(
50 MHz, CDCl ) pair dl: δ = 21.61 (C1, C5), 43.95 (C2, C4), 195.77 (C3) ppm; meso:
3
δ = 19.42 (C1, C5), 43.75 (C2, C4), 195.77 (C3) ppm. MS (GC-MS, CI, NH , 70 eV,
3
1
50 ºC, t = 6.16-7.03 min): m/z (%) = 279 (12, M+N H ), 262 (100, M+NH ), 246 (1,
R 2 7 4
M+2H), 244 (1, M), 182 (6, C H O Br). GC (T = 100 ºC, t = 2 min., r = 10 ºC/min., T
f
5
10
2
i
i
=
200 ºC, t = 30 min.) meso: t = 5.7 min.; pair dl: t = 6.4 min.
f R R
6
.4.4. Synthesis of tert-butyl furan-2-yl-carbamate, (6)
-
20 -

ACCEPTED MANUSCRIPT
In a round-bottom flask equipped with a stirring bar and a Dimroth condenser, 2-furyl
chloride (20 g, 0.14 mol), tert-butyl alcohol (160 mL, 1.7 mol) and sodium azide (10.2g,
0
.16 mol) were placed, under argon atmosphere. The mixture was stirred for 12 h at
room temperature and the formation of the intermediate 2-furylazide as a white solid
was observed. The mixture was heated to reflux (100 ºC) and maintained under these
conditions for additional 12 h. Once 2-furoylazide 5 was completely converted (control
by TLC eluted with hexane/ethyl acetate 4:6), the solvent was removed in vacuo,
obtaining a white solid, which was submitted to a flash column chromatography on
silica gel, eluting with a mixture of hexane and ethyl acetate of increasing polarity. The
elution with a mixture of hexane and EtOAc (9:1), afforded the desired product as a
white solid (21.6 g, 82% yield). The product 6 has to be stored in a cold place and away
from light, in order to avoid its thermal or photochemical decomposition.
MP = 98-99 ºC (ethyl acetate). TLC: R = 0.66 (SiO , hexane/ethyl acetate 4:6,
f
2
developed by ninhydrin). IR (film): ῡ = 3267 (N─H, st), 2980, 1700 (C=O, st), 1546
t
-1 1
(
N─H, def), 1250 ( Bu) cm . H NMR (300 MHz, CDCl ): δ = 1.50 (9H, s, H2'), 6.04
3
1
3
(
1H, brs, H4"), 6.63 (1H, brs, H3"), 7.00-7.12 (1H, m, H5") ppm. C NMR (50 MHz,
CDCl ): δ = 28.2 (C2'), 81.3 (C1'), 95.1 (C4"), 111.2 (C3'), 136.0 (C5'), 145.4 (C2'),
3
1
51.9 (C1) ppm. MS (CI, NH , 70 eV, 150 ºC): m/z (%) = 285 (13, M+NH ), 268 (100,
3 4
t
t
M+1H), 212 (22, M+2H‒ Bu), 167 (36, M+1H‒COO Bu).
The intermediate 2-furoylazide 5 could be transformed, one pot, into the
corresponding carbamate 6 without the necessity to isolate it. However, a pure sample
of 5 was isolated and purified for its physical and spectroscopic characterization.
White solid. MP = 114.5-115 ºC. IR (film): ῡ = 3129 (=C-H, st), 2145 (N=N=N, st as),
1
684 (C=O, st), 1562, 1462 (C-N, st), 1393, 1290, 1231, 1190 (C-O-C, st), 1030, 1001,
-1 1
9
16, 877, 793 cm . H NMR (400 MHz, CDCl ): δ = 6.55 (1H, dd, J = 1.6, J = 3,6,
3
4,5
4,3
H4), 7.26 (1H, dd, J = 0.6, J = 3.6, H3), 7.65 (1H, dd, J = 0.6, J = 1.6, H5) ppm.
3
,5
3,4
5,3
5,4
1
3
C NMR (75 MHz, CDCl ): δ = 112.8 (C4), 120.2 (C3), 145.6 (C2), 148.4 (C5), 162.8
3
(
C1') ppm. MS (CI, NH , 70 eV, 150ºC): m/z (%) = 138 (9, M+H), 137 (6, M), 112 (44,
3
M-CN), 110 (100, M-N ), 95 (89, M-N ), 82 (21, M-CN ). TLC: R = 0.60 (SiO ,
2
3
3
f
2
hexane /ethyl acetate 4:6, developed with ninhydrin reagent).
-
21 -

ACCEPTED MANUSCRIPT
6
.4.5. Reaction of oxyallyl cations (1’) and (3’) with 2-tert-butoxicarbonylaminofuran
(6)
6
.4.5.1. Activation of reducing metals and preparation of metallic couples
3
8
6
.4.5.1.1. Activation of Copper
Copper powder from Sigma-Aldrich (10 g, 0.152 mol) was treated with a solution of
iodine (2 g, 7.8 mmol) in acetone (100 mL). The suspension was stirred for 15 min and
filtered through a Büchner funnel. The obtained violaceous solid was washed with a 1:1
mixture of conc. HCl (37 %) and cold acetone (50 mL) and then with acetone (100 mL)
and diethyl ether (100 mL). The resulting solid was dried under high vacuum and kept
away from light under argon atmosphere. The activated copper has metallic bright and it
was promptly used.
3
9
6
.4.5.1.2. Activation of Zinc
Zinc powder (10 g, 0.152 mol) was suspended in diluted aqueous HCl (50 mL, 3% w/v)
and vigorously stirred for 1 min, observing the release of hydrogen. The process was
repeated two more times and finally the solid was filtered through a Büchner funnel and
washed with distilled water (100 mL), absolute ethanol (100 mL) and diethyl ether (100
mL). The solid was then dried under vacuum in the dark for 3 hours, obtaining a fine
grey solid which was used immediately. Occasionally it was stored in a desiccator under
Ar atmosphere but it is preferable to activate it prior to use.
4
0, 41, 42
6
.4.5.1.3. Preparation of the Zinc-Copper couple
The zinc, activated as before described, (10 g, 0.152 mol) was suspended in an aqueous
solution of copper(II) sulfate (100 mL, 4 % w/v) and vigorously stirred for 15 min. The
zinc powder rapidly darkened turning from light grey to black, and the blue color of the
copper solution completely discolored. The solid was filtered through a Büchner funnel
and successively washed with distilled water (2 x 50 mL), acetone (4x 50 mL), absolute
ethanol (4 x 50 mL) and diethyl ether (4 x 50 mL). Finally, the solid was dried under
vacuum and in the dark for 3 h, obtaining a fine black powder that was immediately
used. Occasionally it was stored in a desiccator, under Ar atmosphere and in the dark,
for a short period of time. Analysis of this solid by atomic absorption showed the
following composition: Zn = 72 %, Cu = 28 %.
-
22 -

ACCEPTED MANUSCRIPT
6
.4.5.2. Cycloaddition by reduction of dihaloketones with Zn/Cu pair
In a double necked flask, fitted with magnetic stirring and nitrogen atmosphere,
freshly activated Zn/Cu pair (210 mg, 3.32 mmol) was added and suspended in
acetonitrile (11 mL). The mixture was cooled down to 0 ºC and the furan derivative (1
mmol) was added at once. Then, dihaloketone (258 mg, 1.06 mmol) was added
dropwise. The reaction mixture was homogenized by stirring and maintained at the
work temperature by using a heating/cooling bath with a temperature stabilizing system.
The reaction was controlled by both TLC and GC. The reaction was considered finished
after observing a constant conversion in successive analyses.
The mixture was cooled to 0 ºC and methylene chloride was added under
constant stirring. The solution was poured over a 1:1 mixture of water / ice (30 mL
approx.) and it was filtered through a porous sintered plate (filtering plate number 4)
under vacuum to remove excess of Zn/Cu powder. The phases were decanted and the
aqueous phase was extracted with methylene chloride (4 x 30 mL) until discoloration of
the organic phase was observed. The organic phases were combined together and
washed successively with a 3 % water solution of NH (3 x 20 mL) until no blue color
3
(due to tetraammincopper(II) complex) was observed in the washing aqueous extracts,
followed by ice-water (2 x 20 mL). Finally, the organic phase was dried over anhydrous
MgSO , filtered and concentrated to dryness, obtaining a product consisting of a single
4
structure or a mixture of diastereoisomers, depending on the furan substrate. The
obtained oil was submitted to a flash column chromatography on silica gel, using
mixtures of hexane and ethyl acetate of increasing polarity to separate products.
6
.4.5.3. Cycloaddition procedure using Fe CO
2 9
In a round bottomed flask fitted with a magnetic stirrer, under argon atmosphere,
compound 6 was placed. Afterwards, inside an Atmosbag® filled with argon, the
pyrophoric diironnonacarbonyl was added to the reactor, (in a molar ratio Fe CO :
2
9
furan 6 = 1.75 : 1), as a bright yellow solid. Then, anhydrous acetonitrile (in a ratio of
.82 mL of ACN : 1 mol Fe CO ) was added and the mixture was stirred for 5 min. 2,4-
0
2
9
Dibromo-3-pentanone, 4, freshly filtered through neutral alumina, was added dropwise
at ‒10 ºC, (in a molar ratio of 1.2 : 1; dibromoketone : furan). The reaction mixture was
stirred at room temperature for 6.5 h. The crude was concentrated to dryness and the
residue was dissolved in acetone. Cerium ammonium nitrate (in a molar ratio CAN :
-
23 -

ACCEPTED MANUSCRIPT
Fe CO = 1 : 1) was added and the reaction mixture was stirred for 5 min. Afterwards,
2
9
the solvent was evaporated under vacuum and the residue was filtered through a short
path of silica gel, and then it was submitted to a flash column chromatography on silica
gel, using mixtures of hexane and diethyl ether of increasing polarity to isolate
cycloadduct 12 in a 76% yield and diastereoselectivity: trans/cis-exo/cis-endo =
19
5
5/40/5.
tert-butyl
N-(2,2,4,4-tetramethyl-3-oxo-8-oxabicyclo[3.2.1]oct-6-en-1-yl}-
carbamate, (8).
1
0"
O
9
"
1
0"
9"
4
"
2
"
O
2'
3
"
O
1"
1'
5
"
N
1
O
2'
8
"
H
6
"
7"
2
'
8
Colourless oil. IR (film): ῡ = 3316, 2978, 2932, 1704, 1471, 1387, 1367, 1332, 1247,
-1 1
1
163, 1054 cm . H NMR (400 MHz, CDCl ): δ = 0.95 (6H, d, J = 6.8 Hz, H10''), 1.05
3
(
6H, d, J = 6.4 Hz, H9''), 1.46 (9H, s, H2'), 1.56-1.63 (1H, m, H6a''), 1.67-1.75 (1H, m,
H7b''), 1.88-1.95 (1H, m, H7a''), 1.98-2.08 (1H, m, H6b''), 2.79-2.85 (1H, m, H4''), 3.68
1H, d, J = 5.6 Hz, H2''), 4.47 (1H, dd, J = 4.8 Hz, J = 7.6, Hz H5''), 5.24 (1H, brs,
(
1
2
1
3
NH) ppm. C NMR (100 MHz, CDCl ): δ = 9.0 (C9''), 9.8 (C10''), 24.2 (C6''), 28.1
3
(
C2'), 31.6 (C7''), 49.4 (C4''), 52.9 (C2''), 78.2 (C5''), 80.1 (C1'), 94.2 (C1''), 154.0 (C1),
09.1 (C3'') ppm. MS (CI, 70 eV, 150 ºC): m/z (%) = 296 (23, M+1), 257 (98), 240 (86,
M-C H ), 196 (100, M-C H O ). Anal. Calcd for C H NO : C 65.06, H 8.53, N 4.74
2
4
8
5
8
2
16 25
4
%
. Found: C 65.10, H 8.55, N 4.71 %. TLC: R = 0.74 (SiO , hexane/diethyl ether 3:7,
f 2
three elutions. Developed by ninhydrin reagent).
cis-7-Isopropylidene-8,8-dimethyl-2,6-dioxabicyclo[3.3.0]octan-3-one, (7)
-
24 -

ACCEPTED MANUSCRIPT
3
Colourless oil IR (film): ῡ = 2975 (H-Csp ), 1786 (C=O), 1697 (C=C), 1467, 1370,
1
1
314, 1193, 1129, 1083, 1057, 1038. H NMR (400 MHz, CDCl ): δ = 1.23 (3H, s,
3
H2"), 1.46 (3H, s, H3"), 1.59 (3H, s, H1'), 1.62 (3H, s, H2'), 2.73-2.76 (2H, m, H4),
13
4
.44 (1H, d, J = 4.0 Hz, H1), 4.82-4.84 (1H, m, H5) ppm. C NMR (100 MHz,
CDCl ): δ = 17.0 (C2'), 18.9 (C1'), 22.6 (C3"), 25.1 (C2"), 37.1 (C4), 44.3 (C8), 75.4
3
(
C5), 93.0 (C1), 101.3 (C1"), 153.5 (C7), 175.0 (C3) ppm. MS (CI, 70 eV, 150 ºC): m/z
%) = 197 (M+1, 100). Anal. Calcd for C H O : C 67.32, H 8.22 %. Found: C 67.29,
(
1
1
16
3
H 8.25 %. TLC: R = 0.62 (SiO , hexane/diethyl ether 3:7, three elutions; developed by
f
2
ninhydrin reagent).
1R*, 5R*, 7R*)-7-Isopropyl-7-hydroxy-8,8-dimethyl-2,6-dioxabicyclo[3.3.0]octan-
-one, (17)
(
3
3
Colourless oil IR (film): ῡ = 3480 (O-H), (H-Csp ), 1779 (C=O), 1458, 1366, 1310,
1
1
195, 1123, 1090, 1061, 1040. H NMR (400 MHz, CDCl ): δ = 0.94 (3H, d, J = 6.8
3
Hz, H2"), 0.99 (3H, d, J = 6.8 Hz, H3"), 1.04 (3H, s, H1'), 1.31 (3H, s, H2'), 1.95-2.04
(1H, m, H1"), 2.26 (1H, brs, OH), 2.68-2.70 (2H, m, H4), 4.50 (1H, d, J = 5.4 Hz, H1),
1
3
4
1
.79-4.83 (1H, m, H5) ppm. C NMR (100 MHz, CDCl ): δ = 16.8 (C3"), 17.3 (C2"),
3
8.9 (C2'), 22.3 (C1'), 33.2 (C1"), 38.7 (C4), 48.6 (C8), 74.2 (C5), 93.0 (C1), 109.8
(C7), 176.1 (C3) ppm. MS (CI, 70 eV, 150 ºC): m/z (%) = 214 (M, 53, 4). Anal. Calcd
for C H O : C 61.66, H 8.47 %. Found: C 61.70, H 8.46 %. TLC: R = 0.48 (SiO ,
1
1
18
4
f
2
hexane/diethyl ether 3:7, three elutions; developed by ninhydrin reagent).
cis-7-Cyclohexylidene-8-spirocyclohexane-2,6-dioxabicyclo[3.3.0]octan-3-one, (9)
-
25 -

ACCEPTED MANUSCRIPT
Colourless oil. IR (film): ῡ = 2923, 2852, 1785 (C=O), 1686 (C=C), 1450, 1320, 1256,
1
1
1
194, 1150, 1047. H NMR (400 MHz, CDCl ): δ = 1.23-1.29 (1H, m, cyclohexyl),
3
.40-1.60 (7H, m, cyclohexyl), 1.67-1.80 (4H, m, cyclohexyl), 1.87-1.89 (1H, m,
cyclohexyl), 2.02-2.24 (7H, m, cyclohexyl), 2.73 (1H, d, J = 4.0 Hz, H4 ), 2.73 (1H,
a
1
3
brs, H4 ), 4.70 (1H, dd, J = J = 3.6 Hz, H5), 4.88 (1H, d, J = 3.2 Hz, H1) ppm. C
b
1
2
NMR (100 MHz, CDCl ): δ = 23.5, 23.9, 25.4, 26.9, 27.6, 28.0, 28.2, 28.9, 30.2 and
3
3
1
2.7 (methylenes from cyclohexyl group); 36.8 (C4), 75.7 (C5), 88.0 (C1), 110.8 (C1''),
52.4 (C7), 175.5 (C3) ppm. MS (CI, 70 eV, 150 ºC): m/z (%) = 277 (M+1, 100). Anal.
Calcd for C H O : C 73.88, H 8.75 %. Found: C 73.91, H 8.73 %. TLC: R = 0.72
1
7
24
3
f
(
SiO , hexane/diethyl ether 3:7, three elutions; developed by ninhydrin reagent).
2
6
.4.6. Cycloaddition of 2,4-dibromo-2,4-dimethyl-3-pentanone with furan (4).
Synthesis of 2,2,4,4-tetramethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one, (14)
1
1
O
3
10
1
2
9
4
2
1
O
8
5
6
7
1
4
Following the before-described reaction procedure that uses Zn/Cu couple as reducing
agent, , 2,4-dibromo-2,4-dimethyl-3-pentanone 1 (271 mg, 1.06 mmol), dissolved in dry
acetonitrile (5 mL), was reacted with dry furan (770 µL, 10.6 mmol) in the presence of
freshly prepared Zn/Cu pair (210 mg, 3.32 mmol) as reducing agent at 20 ºC under
nitrogen atmosphere. After 4.5 h of reaction time (control by TLC and GC), the reaction
mixture was submitted to the usual work-up, obtaining a crude product, which was also
submitted to a flash column chromatography on silica gel, eluting with mixtures of
hexane and ethyl acetate of increasing polarity. With hexane/ EtOAc 9:1 compound 14
was isolated as a pure product. Colourless oil (109 mg, 57% yield). Analysis by NMR
and GC of the crude reaction product and also of the chromatographic fractions did not
show the presence of [3+2]-cycloadduct 13.
IR (KBr): ῡ = 2969, 2932, 2873, 1713 (C=O, st), 1470, 1381, 1364, 1067, 943, 926, 908
-1 1
cm . H NMR (200 MHz, CDCl ): δ = 0.93 (6H, s, H9 y H11), 1.36 (6H, s, H10 and
3
1
3
H12), 4.42 (2H, s, H1 and H5), 6.37 (2H, s, H6 and H7). C NMR (50 MHz, CDCl ): δ
3
=
21.0 (C9 and C12), 26.7 (C10 and C11), 51.4 (C2 and C4), 86.4 (C1 and C5), 133.7
26 -
-

ACCEPTED MANUSCRIPT
(
C6 and C7). MS (GC-MS(CI), NH , 70 eV, 150ºC): m/z, (%) = 198 (8, M+NH ), 181,
3
4
+
(
7, M+1), 180 (M ). Anal. Calcd for C H O : C 73.30, H 8.95 %. Found: C 73.29, H
11 16 2
8
.97 %.GC (100 ºC, 1 min, 10 ºC/min, 250 ºC, 1 min): t = 7.32 min. TLC (SiO ,
R 2
hexane/ ethyl acetate 8:2. Developed as a purple spot by anisaldehyde reagent): R =
f
0
.73.
6
.4.7. Cycloaddition of 1',1"-dibromodicyclohexylketone with furan (4). Synthesis
of 2,4-bis(spirocyclohexane)-8-oxabicyclo[3.2.1]oct-6-en-3-one, (16)
O
4
"
6"
6'
2'
4'
5
"
5'
3'
3
2
"
1" 4
2 1'
3
"
O
8
5
6
1
7
16
In an oven-dried 50 mL flask, fitted with magnetic stirring and argon atmosphere,
freshly prepare Zn/Cu couple (210 mg, 3.32 mmol) was placed suspended in dry
acetonitrile (7 mL). Dry furan (770 µL, 10.6 mmol), was added by syringe at room
temperature. The system was cooled down to ‒44 ºC and Me SiCl (135 µL, 1.06 mmol)
3
was added. Afterwards, 1',1"-dibromo-dicyclohexylketone 6 (373 mg, 1.06 mmol),
dissolved in a acetonitrile-dichloromethane mixture 4:1 (5 mL) were added dropwise.
The reaction mixture was stirred at ‒44 ºC for 1h (control by GC). The resulting
reaction mixture was percolated through a short pad (2 cm) of neutral alumina, in order
to remove the metallic particles, washing the column with ethyl acetate. The organic
phase was concentrated to dryness and submitted to a flash column chromatography on
silica gel, eluting with mixtures of hexane and ethyl acetate of increasing polarity. Pure
product 16 was isolated with hexane/EtOAc 95:5 as a thick oil (176.5 mg, 64% yield).
Careful analysis by high field NMR and GC of both the crude reaction mixture and the
chromatographic fractions did not show the presence of [3+2}-cycloadduct 15.
IR (KBr): ῡ = 2929, 2857, 1697, (C=O, st), 1451, 1325, 1190, 1146, 1130, 1119, 1047,
-1 1
9
82, 910 cm . H NMR (200 MHz, CDCl ): δ = 1.31-1.74 (20H, several overlapped m,
3
H2', H2", H3', H3", H4', H4", H5', H5", H6', H6"), 4.92 (2H, s, H1, H5), 6.37 (2H, s, H6
13
and H7) ppm. C NMR (50 MHz, CDCl ): δ = 21.0, 21.3, 21.5, 25.3, 25.5, 25.6, 29.4,
3
2
9.6, 33.0, 33.7 (C2', C2", C3', C3", C4', C4", C5', C5", C6', C6"), 55.3 (C2, C4), 81.3
(
C1, C5), 113.4 (C6, C7), 217.0 (C3) ppm. MS (GC-MS(CI), NH , 70 eV, 150ºC): m/z
3
-
27 -

ACCEPTED MANUSCRIPT
(
%) = 295 (15, M+N H ), 278 (100, M+NH ), 261 (11, M+1). Anal. Calcd for
2
7
4
C H O : C 78.40, H 9.30 %. Found: C 78.18, H 9.12 %. GC (100ºC, 1 min, 10
17
24
2
ºC/min, 250C, 1 min): t = 18.25 min. TLC (SiO , hexane / ethyl acetate, 8:2): R = 0.81
R
2
f
(developed as a purple spot by anisaldehyde reagent).
7
. Supporting Information
Tables S1, S2 and S3 as well as Figures S1, S2 and S3, relative to the energy, atomic
charges and HOMO-LUMO computer calculations of reacting species 1’ and 6 and also
1
13
of intermediate I are included as supporting information. Copies of H-, C NMR, IR
and MS spectra of the herein described products are also included. A copy of these data
may be obtained free of charge from the Web page of the publisher.
8
. References
1
a) Mereyala, H. B.; Gadikota, R. R.; Joe, M.; Arora, S. K.; Dastidar, S. G.;
Agarwal, S. Bioorg. Med. Chem. 1999, 7, 2095-2103; b) Popsavin, V.; Grabez, S.;
Popsavin, M.: Krstic, I.; Kojic, V.; Bogdanovic, G.; Divjakovic, V. Tetrahedron
Letters 2004, 45, 9409-9413; c) Fernández de la Pradilla, R.; Fernández, J.; Viso,
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B.; Gadikota, R. R.; Joe, M.; Arora, S. K.; Dastidar, S. G.; Agarwal, S. Bioorg.
Med. Chem. 1999, 7, 2095-2103; e) Mihovilovic, M. D.; Bianchi, D. A.; Rudroff,
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Lett., 1997, 38, 819-820; g) Bruns, R.; Wernicke, A.; Köll, P. Tetrahedron, 1999,
55, 9793-9800.
2
3
a) Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002, 124, 9718-9719; b) Hayes,
P. Y.; Chow, S.; Rahm, F.; Bernhardt, P. V.; De Voss, J. J.; Kitching, W. J. Org.
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a) Yang, P.; Yao, M.; Li, J.; Li, Y.; Li, A. Angew. Chem. Int. Ed. 2016, 55, 6964 –
6968; b) Goh, S. S.; Chaubet, G.; Gockel, B.; Cordonnier, M. C. A.; Baars, H.;
Phillips, A. W.; Anderson, E. A. Angew. Chem. Int. Ed. 2015, 54, 12618-12621.
4
5
Mereyala, H. B.; Gadikota, R. R.; Sunder, K. S.; Shailaja, S. Tetrahedron 2000,
56, 3021-3026.
a) Cagnolini, C.; Ferri, M.; Jones, P. R.; Murphy, P. J. Tetrahedron 1997, 53,
4815-4820; b) Lievre, C.; Humez, S.; Frechou, C.; Demailly, G. Tetrahedron Lett.
1997, 38, 6003-6006.
-
28 -