Merging metathesis and photochemical Csp3-H activation: Access to masked β-formyl hexanolides and their rearrangement to furofuranones

Article abstract of DOI:10.1016/j.tet.2018.06.040

β-Masked formyl hexanolides were prepared by a three-step sequence including esterification of homoallylic alcohols, ring-closing metathesis and the photochemically induced addition of dioxanyl radical. When treated under oxidative conditions, the adducts underwent cleavage of the ketal group leading after rearrangement to parent furofuranones, structures found in some biological active compounds.

Full text of DOI:10.1016/j.tet.2018.06.040

Accepted Manuscript
3
Merging metathesis and photochemical Csp -H activation: Access to masked β-
formyl hexanolides and their rearrangement to furofuranones
Quentin Glenadel, Youssef Nassar, Ludovic Raffier, Sebastiaan Veys, Olivier Piva
PII:
S0040-4020(18)30740-3
10.1016/j.tet.2018.06.040
TET 29636
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 March 2018
Revised Date: 14 June 2018
Accepted Date: 15 June 2018
Please cite this article as: Glenadel Q, Nassar Y, Raffier L, Veys S, Piva O, Merging metathesis and
3
photochemical Csp -H activation: Access to masked β-formyl hexanolides and their rearrangement to
furofuranones, Tetrahedron (2018), doi: 10.1016/j.tet.2018.06.040.
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Merging metathesis and photochemical Csp3-
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H activation: Access to β-formyl hexanolides
and their rearrangement to furofuranones
Quentin Glenadel, Youssef Nassar, Ludovic Raffier, Sebastiaan Veys and Olivier Piva*
Université de Lyon – ICBMS – UMR 5246 CNRS –France

1
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Tetrahedron
journal homepage: www.elsevier.com
Merging metathesis and photochemical Csp3-H activation: Access to masked β-
formyl hexanolides and their rearrangement to furofuranones
Quentin Glenadela , Youssef Nassara , Ludovic Raffiera , Sebastiaan Veysa , and Olivier Pivaa,
aUniversité de Lyon, Université Claude Bernard Lyon 1,CNRS, CPE Lyon, INSA-Lyon, UMR 5246, ICBMS, Bat. Raulin, 43, Bd du 11 novembre 1918, F-69622
Villeubanne cedex, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
β-Masked formyl hexanolides were prepared by a three-step sequence including esterification of
homoallylic alcohols, ring-closing metathesis and the photochemically induced addition of
dioxanyl radical. When treated under oxidative conditions, the adducts underwent cleavage of
the ketal group leading after rearrangement to parent furofuranones, structures found in some
biological active compounds.
Available online
2018 Elsevier Ltd. All rights reserved
.
Keywords:
Ring-closing metathesis
Lactones
Radical addition
Photochemistry
Deprotection
———
Corresponding author. Tel.: +33-047-244-8136; e-mail: piva@university-lyon1.fr

2
Tetrahedron
ACCEPTED MANUSCRIPT
O
1. Introduction
O
O
O
Unsaturated five and six membered-ring lactones constitute
two important classes of compounds largely present in the
nature.1 They are also considered as promising scaffolds for
the access to more elaborated targets. Since the discovery and
availability of well-defined catalysts, ring-closing metathesis
has emerged as a powerful method to access a large number of
unsaturated heterocyclic structures, including these lactones.2-4
Furthermore, the newly created double bond can be
subsequently functionalized to deliver more sophisticated
compounds.5 In connection with our interest in metathesis but
also in photochemical reactions, we have merged these two
topics to develop a synthesis of masked formyl hexanolides,
which could be further transformed into furofuranones. Such
bicyclic subunits have been found in numerous natural
products, which exhibit for a large part of them, interesting
O
O
O
1
H
1
O
R
R
2
2
1
R
R
R
2
O
O
R
10
9
8
O
O
OH
O
O
2
1
R
1
1
R
2
R
R
2
R
R
7
6
5
Scheme 1. Planned synthetic pathway to furofuranones 10.
The conversion of 7 into 8 is based on previous results18
already conducted on butenolides and other electron deficient
alkenes. Photochemical hydrogen abstraction on 1,3-dioxolane
promoted by benzophenone could generate a highly stabilized
radical which underwent a regio- and diastereoselective
addition onto the conjugated double bond. (Scheme 2).
properties. For exemple, 15-oxoscutecyprol
A
1,
a
neoclerodane derivative is an effective antifeedant compound
with potential interest for biological control against pests.6
Norrisolide 2 has a major impact on the Golgi apparatus in
eukaryotic cells, and induces its irreversible fragmentation.7
Compound 3 which possesses a 5,6-seco tremulane skeleton8
as well as conosilane A 4,9 have been recently isolated from
cultures of basidiomycete Conocybe siliginea. Therefore, due
to their biological properties, access to furofuranones and
related structures has been the subject of intense investigations
over the past thirty years.10-17
O
O
hν
O
O
O
O
benzophenone
+
R
O
R
O
Scheme 2.
butenolides
Photochemical addition of 1,3-dioxolane on
.
H
O
O
HO
O
The benefits of this process are manifold. First, the
conditions are mild avoiding the use of strong bases on highly
sensitive substrates. Furthermore, the process can be conducted
in the presence of only catalytic amounts of benzophenone as a
promoter.19 Gratifying, the reaction was carried out under
visible light, avoiding the use of special equipments. In the
intensive field of C-H activation and functionalization of
organic substrates at a specific position, the photochemical
approach appears also extremely attractive in term of cost,
compared to other transformations which usually require the
use of noble metals such as palladium or ruthenium even in
catalytic amounts.
O
O
H
O
O
O
O
H
3
O
O
O
OAc
O
O
OAc
AcO
O
1
2
4
Figure 1. Natural products possessing a furofuranone subunit.
Known secondary homoallylic alcohols 5a-b were
efficiently prepared by condensation of allylzinc on aldehydes
under Barbier conditions.20 Esterification21 with acryloyl
chloride furnished homoallylic acrylates 6a-b. RCM was then
carried out by reflux of dichloromethane and in presence of 5
mol% of Grubbs type I catalyst GBI (Fig. 2). After 4 to 6 hours
of heating, the unsaturated lactones 7a-b were obtained with
high yields (Table 1).
2. Results and discussion
We envisaged the access to furofuranones as illustrated in
scheme 1. Readily available homoallylic acrylates 6 could
deliver the corresponding α,β−unsaturated δ-valerolactones 7
by ring-closing metathesis (RCM). It was anticipated that the
addition of a highly stabilized dioxolanyl radical generated by
hydrogen abstraction from the solvent, could regioselectively
occur to furnish the expected masked β-formyl adducts 8. A
selective deprotection of the ketal group, followed by a
rearrangement of the formyl lactones could deliver the
corresponding furofuranones 10.
PCy
Ru
3
Cl
Cl
Ph
GBI
PCy
3
Figure 2. Grubbs type I catalyst.
Table 1. Synthesis and RCM of acrylates 6a-b.

3
Tetrahedron
ACCEPTED MANUSCRIPT
O
intermediate which abstracted one hydrogen atom. After
chromatography, compounds 8a-b were tentatively purified by
flash-chromatography to furnish mixture of syn/anti
O
O
OH
Cl
O
1
O
a
R
GB (cat.)
I
DMAP
1
stereoisomers but still contaminated with some minor
dioxolane derivatives (Table 3).
1
CH Cl
40°C
R
Et N
3
CH Cl
2
R
2
2
2
5a-b
6a-b
7a-b
Table 3. Addition of dioxalanyl radical onto lactones 7a-b
5
R1
6
Yielda
7
Yielda
76%
O
5a
5b
n-C8H17
6a
6b
61%
75%
7a
7b
O
m-CH3O-C6H4
83%
O
O
R
a Isolated yield
O
O
1
H
O
hν
O
In parallel, formation of spiranic lactones22 was carried out
from cyclic tertiary homoallylic alcohols 5c-f, easily prepared
by treatment of cycloalkanones with in situ generated allyl zinc
reagent. Esterification of these hindered alcohols was achieved
by deprotonation with n-BuLi, followed by reaction with
acryloyl chloride.21b By this way, esters 6c-f were isolated in
acceptable yields. Successful RCM required at least a suitable
conformation by the substrate for which the two double bonds
are close. We were highly pleased to notice that even in the
presence of less reactive Grubbs type I catalyst GBI, the
reaction occurred rapidly to furnished the spiranic lactones,
without the need of additives as titanium isopropoxide. This
efficiency could be attributed to a Thorpe Ingold effect which
allows a favourable conformation to the substrates.23
O
benzophenone
R
1
O
O
7
H
R
1
O
8
7
R1
n-C8H17
m-CH3O-C6H4
8
syn:antia
34:66
7a
7b
8a
8b
25:75
a Determined by 1H-NMR on the isolated product.
To have an access to the free formyl derivatives, various
conditions were tested to deprotect the ketal group. Initial
attempts have been carried out on compound 8a under acidic
conditions leading to the recovery of starting material or
decomposition when performed at rt or higher temperatures
respectively. Reactions involving oxidative deprotection were
next considered.24 According to the literature, cerium
ammonium nitrate (CAN) can promote single electron transfer
to generate a radical cation which can be oxidized in the
middle and undergo the subsequent deprotection.
Table 2. Synthesis and RCM of acrylates 6c-f.
O
OH
Br
Zn
( )
n
THF, NH Cl(aq.), r.t.
4
( )
R
n
R
5c-f
O
O
O
O
1) n-BuLi
THF, -78°C
2)
Cl
GBI
(8 mol%)
O
O
CAN
(2.5 equiv.)
O
O
CH Cl
2
2
O
40°C
( )
O
R
n
R
( )
n
R
R
CH CN, H O
3
2
H
H
O
O
6c-f
7c-f
r.t.
70°C
O
+
8a
5
R
H
H
n
Yield%a
Quant.
90
6
Yield%a
47
7
Yield%a
75
O
O
+
H
5c
5d
5e
0
1
1
1
6c
6d
6e
6f
7c
7d
7e
7f
O
O
H O
2
O
O
R
R
R
57
87
H
H
O
H
O
O
+
t-Bu
68
72
77
O
H
O
5f
Ph
76
46
76
O
O
H
a
O
Isolated yield
+
O
H
H
H
R
Radical addition was first carried out on lactones 7a-b. The
reaction requires usually 4 to 6 hours of irradiation in 1,3-
dioxolane as solvent and under argon to prevent competitive
oxidations. The attack of the stabilized radical occurred
exclusively on the β-position to furnish a new radical
10a (16% from 7a)
Scheme 3. Oxidative deprotection of 8a and direct access to 10a.
As expected, β-formyl lactone 8a, when treated by CAN in
a 2:1 mixture of acetonitrile and water, was converted to a new

4
Tetrahedron
ACCEPTED MANUSCRIPT
structure. 1H-NMR spectra analysis was not consistent with the
presence of a free aldehyde function, but revealed nevertheless
Compounds 10c-f were obtained in the range of 40 to 48%
yield. It should be pointed out that these values result from
the cleavage of the dioxanolyl subunit. On 13C-NMR spectra, three-step processes which include in each case,
a
signal at 108 ppm was characteristic of the new ketal group of
furofuranones (Scheme 3). Based on these observations and
regioselective addition of the dioxanyl radical, a deprotection
of the ketal group and finally the rearrangement of formyl
previous results in the literature,12,14,25 it was assumed that the lactones to furofuranones.
formation of the furofuranone
occurred during the
Additionally, to explore an alternative pathway to β-formyl
hexanolides 9 from lactones 7, we investigated a Stetter type
deprotection step and can be rationalized by the following
mechanism (Scheme 4). This procedure was also applied to 8b reaction26 by using the conditions reported by Chi et al. on
but unfortunately, decomposition of the starting material was
solely observed. In this case, a competitive oxidation could
take place on the additional benzylic position leading to
degradation.
chalcones.27 D-Glucose combined with commercially available
thiazolium salt 11 was used to generate a formyl anion in
CH3CN under microwaves activation (Scheme 5).
Unfortunately, when performed on 7d, the starting material
was integrally recovered even after prolonged microwave
H
HO
+
irradiation.
O
OH
2
OH
OH
O
O
O
H
O
O
O
+
H
R
N
S
I
R
+
+
H
O
O
O
O
11 (0.2 equiv.)
D-Glucose (1 equiv.)
O
H
O
CHO
O
H
O
H
R
R
CH CN, µν
3
10a
130°C, 30 min.
7d
9d
Scheme 4. Rearrangement of formyllactone into furofuranone 10.
Scheme 5. Alternative approach to β-formylhexanolide.
Spirohexenolides 7c-f were submitted to the photochemical
assisted radical addition of dioxolane furnishing β-masked
formyl lactones 8c-f which were also contaminated by minor
side-products of similar polarity. After removal of the solvent,
the crude product was submitted to CAN oxidation to furnish
furifuranones 10c-f (Table 4).
3. Conclusions
In conclusion, we have reported the synthesis of protected β-
formyl hexanolides by merging a RCM and an intermolecular
regioselective dioxanyl radical addition. This overall process
which combines an organometallic catalyzed cyclization and a
photochemical reaction can be considered as an attractive
green process. It demonstrates once again the interest to
develop photochemical procedures and reinforce its role in the
field of sustainable chemistry. Consequently, deprotection of
the ketal group was achieved under oxidative conditions
leading after rearrangement to furofuranones in moderate
yields.
Table 4. Addition of dioxalanyl radical onto spiranic lactones 7c-f
O
O
O
O
O
O
hν
O
benzophenone
( )
n
O
R
( )
n
R
8c-f
7c-f
4. Experimental section
O
O
O
4.1 General
O
O
CAN
All commercially available compounds were used without
further purification. Solvent were dried according to standard
procedures. Hexanes refer to a hydrocarbon mixture with a
boiling range of 40-60°C. Column chromatography was
performed with silica gel (0.040-0.063 mm, ROTH). NMR
spectra were recorded at 293 K, using a 300 MHz spectrometer
(Bruker, AMX 300). Shifts are referenced relative to
deuterated solvent residual peaks. Low and high resolutions
(BR and HRMS) mass spectra were recorded in the positive
mode using a Bruker MicrOTOF-Q II XL spectrometer. IR
spectra were recorded on a Perkin Elmer Spectrum One
apparatus. Irradiation were performed in pyrex vessel with a
500W white halogen lamp (Massive Faro model with a
maximum of emission between 300 and 800 nm).
H
CH CN
3
( )
H O
2
O
R
n
( )
n
R
10c-f
Yielda
9
7
R
H
n
0
1
1
1
10
7c
7d
7e
7f
10c
10d
10e
10f
48%
46%
48%
40%
H
t-Bu
Ph
4.2. Allylation of cycloalkanones – General procedure.28
a Isolated yield
To a stirred solution of the cycloalkanone (12.9 mmol) in a 1:1
THF and saturated ammonium chloride solution (0.2M), were

5
Tetrahedron
ACCEPTED MANUSCRIPT
added allyl bromide (19.3 mmol) and zinc (1.27 g, 19.3 mmol).
The whole mixture was stirred for 16 h at room temperature.
After complete disappearance of the starting material (TLC
control), THF was removed by concentration. After dilution
with ether, the aqueous layer was extracted with ether (2x 10
mL). The organic phase was further dried with MgSO4. After
filtration and concentration, the crude product was purified by
flash-chromatography over silica with a 90:10 hexanes :
EtOAc solution as eluent to give the expected compounds.
Spectroscopic data were in agreement with literature: 5c29(78
%), 5d30 (93%), 5e31 (67%), 5f32 (71%).
Colorless oil. Yield: 47% (343 mg isolated from 5c (511
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 6.30 (dd, J
1
= 17.3, 1.7 Hz, 1H), 6.04 (dd, J = 17.3, 10.4 Hz, 1H),
5.84-5.70 (m, 2H), 5.10-5.01 (m, 2H), 2.76 (dt, J = 7.3,
1.2 Hz, 2H), 2.17-2.08 (m, 2H), 1.81-1.53 (m, 6H). 13C
NMR (75 MHz, CDCl3): δ (ppm) = 165.7, 133.9, 130.1,
129.7, 118.0, 92.2, 41.5, 37.4, 24.1. HRMS (ESI): m/z
[M+Na+] calcd for C11H16NaO2: 203.1043; found:
203.1038.
4.8. 1-Allylcyclohexyl acrylate (6d)
4.3 Esterification of secondary homoallylic alcohols – General
procedure.21a
Yellow oil. Yield: 57% (180 mg isolated from 5d (290
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 6.32 (dd, J
1
= 17.3, 1.7 Hz, 1H), 6.07 (dd, J = 17.3, 10.4 Hz, 1H),
5.82-5.68 (m, 2H), 5.09-5.02 (m, 2H), 2.69 (dt, J = 7.3,
1.1 Hz, 2H), 2.25 (d, J = 12.2 Hz, 2H), 1.62-1.21 (m, 8H).
13C NMR (75 MHz, CDCl3): δ (ppm) = 165.4, 133.1,
130.3, 129.6, 118.3, 83.8, 42.2, 34.6, 25.6, 21.9. HRMS
(ESI): m/z [M+Na+] calcd for C12H18NaO2: 217.1199;
found: 217.1193.
To a solution of homoallylic alcohol 5a-b (2 mmol) in DCM
(10 mL) was added triethylamine (2.2 mmol) and DMAP (0.1
mmol). After cooling to 0°C, acryloyl chloride (4 mmol) was
dropwise added. The resulting mixture was stirred at r.t. for 4h.
After hydrolysis with a saturated aqueous solution of
ammonium chloride, the aqueous layer was extracted with
DCM. The organic layers were successively washed with
water and brine, then dried over MgSO4. After filtration and
concentration, the resulting solution was purified by flash
chromatography on silica (10/90 EtOAc/hexanes).
4.9. 1-Allyl-4-t-butylcyclohexyl acrylate (6e)
Colorless oil. Yield: 72% (260 mg isolated from 5e (284
1
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 6.28 (dd, J
4.4. 4-Dodec-1-enyl acrylate (6a)
= 17.3, 1.7 Hz, 1H), 6.02 (dd, J = 17.3, 10.4 Hz, 1H),
5.75-5.66 (m, 2H), 5.04-4.98 (m, 2H), 2.64 (d, J = 7.5 Hz,
2H), 2.41-2.37 (m, 2H), 1.58-1.55 (m, 2H), 1.24-1.16 (m,
4H), 1.01-0.93 (m, 1H), 0.80 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ (ppm) = 165.2, 133.0, 130.2, 129.4, 118.2, 83.0,
47.3, 42.8, 34.7, 32.4, 27.5, 22.3. HRMS (ESI): m/z
[M+Na+] calcd for C16H26NaO2: 273.1825; found:
273.1821.
Colorless oil. Yield: 61% (318 mg isolated from 5a (401
1
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 6.39 (dd, J
= 17.3, 1.6 Hz, 1H), 6.10 (dd, J = 17.3, 10.4 Hz, 1H),
5.83-5.69 (m, 2H), 5.11-5.03 (m, 3H), 2.37-2.31 (m, 2H),
1.59-1.57 (m, 2H), 1.28-1.21 (m, 12H), 0.87 (t, J = 6.9
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ (ppm) = 166.1,
133.9, 130.5, 129.0, 117.8, 73.8, 38.8, 33.7, 32.0, 29.6,
29.4, 25.4, 22.8, 14.3. HRMS (ESI): m/z [M+Na+] calcd
for C15H26NaO2: 261.1825; found: 261.1820.
4.10. 1-Allyl-4-phenylcyclohexyl acrylate (6f)
Colorless oil. Yield: 37% (504 mg isolated from 5f (1070
4.5. 1-(3-Methoxyphenyl)but-3-enyl acrylate (6b)33
1
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 7.32-7.16
(m, 5H), 6.38 (dd, J = 17.3, 1.6 Hz, 1H), 6.13 (dd, J =
17.3, 10.3 Hz, 1H), 5.86-5.70 (m, 2H), 5.13-5.06 (m, 2H),
2.75 (d, J = 7.4 Hz, 2H), 2.57-2.49 (m, 1H), 1.79-1.63 (m,
4H), 1.57-1.21 (m, 4H). 13C NMR (75 MHz, CDCl3): δ
(ppm) = 165.0, 146.7, 132.7, 130.0, 129.6, 128.3, 126.7,
126.0, 118.4, 82.4, 43.3, 42.7, 34.5, 29.0. HRMS (ESI):
m/z [M+Na+] calcd for C18H22NaO2: 293.1512; found:
293.1512.
Colorless oil. Yield: 71% (1.70 g isolated from 5b (1.85
g)). H NMR (300 MHz, CDCl3): δ (ppm) = 7.29-7.24 (m,
1
1H), 6.95-6.88 (m, 2H), 6.83 (ddd, J = 8.1, 2.5, 1.1 Hz,
1H), 6.43 (dd, J = 17.3, 1.6 Hz, 1H), 6.15 (dd, J = 17.3,
10.4 Hz, 1H), 5.87-5.81 (m, 2H), 5.72 (ddt, J = 17.1, 10.2,
7.0 Hz, 1H), 5.12-5.03 (m, 2H), 3.81 (s, 3H), 2.74-2.54
(m, 2H). 13C RMN (75 MHz, CDCl3): δ (ppm) = 165.4,
159.7, 141.7, 133.3, 131.0, 129.6, 128.6, 118.9, 118.2,
113.3, 112.4, 75.3, 55.3, 40.9. HRMS (ESI): m/z [M+Na+]
calcd for C14H16NaO3: 255.0992; found: 255.0980.
4.11. Metathesis:
4.6. Esterification of tertiary alcohols
procedure.21b
–
General
A solution of acrylate 6 (1.85 mmol) in dichloromethane (185
mL) was deoxygenated by bubbling an argon stream through
the solution for 10 min. Grubbs type I catalyst (120 mg, 0.15
mmol) was added in one portion, and the resulting
homogeneous solution was heated for 2-4 h. After
concentration, lactone 7 was isolated by flash-chromatography
on silica (EtOAc/hexanes, 20:80).
A solution of the homoallylic alcohol (2.89 mmol) in dry THF
(40 mL) was treated with a 1.6 M solution of n-BuLi in hexane
(2.1 mL, 3.47 mmol) at –78 °C for 1 h. Acryloyl chloride (0.35
ml, 4.33 mmol) was then added, and the mixture was warmed
to r.t. and stirred overnight. After hydrolysis with a saturated
NaHCO3 solution, the organic layer was separated and the
aqueous layer was extracted with Et2O (3 × 12 mL). After
drying over anhydrous MgSO4, the organic layers were
concentrated under reduced pressure and the crude product
was purified by column chromatography using 90:10
Petroleum ether: EtOAc as eluent to give the corresponding
acrylate.
4.12. 6-Octyl hexenolide (7a)
Brown oil. Yield: 76% (195 mg isolated from 6a (290
1
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 6.90-6.84
(m, 1H), 6.02 (dt, J = 9.7, 1.7 Hz, 1H), 4.46-4.37 (m, 1H),
2.35-2.31 (m, 2H), 1.68-1.60 (m, 2H), 1.34-1.21 (m, 12H),
0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
(ppm) = 164.8, 145.2, 121.6, 78.2, 35.0, 32.0, 29.6, 29.6,
4.7. 1-Allylcyclopentyl acrylate (6c)

6
Tetrahedron
ACCEPTED MANUSCRIPT
29.5, 29.4, 25.0, 22.8, 14.3. HRMS (ESI): m/z [M+Na+]
calcd for C13H22NaO2: 233.1512; found: 233.1509.
4.13. 6-(3-Methoxyphenyl) hexenolide (7b)34
A solution of unsaturated lactone 7 (0.9 mmol) dissolved
in 1,3-dioxolane (100 mL) was placed in a 250 mL pyrex
balloon equipped with a cooling system. Benzophenone (
25 mg, 0.14 mmol.) was added and the resulting clear
solution was bubbled with argon for 10 min. Irradiation
was carried out until complete disappearance of the
starting material (TLC control). The solution was
concentrated under vacuum. Compounds 8a and 8b were
tentatively purified by flash-chromatography on silica
(eluant 20:80 AcOEt:hexanes). Other lactones 8c-8f
obtained as crude mixture, were directly implicated in the
next deprotection / rearrangement procedure without
further purification.
Brown oil. Yield: 89% (384 mg isolated from 6b (490
1
mg)). H RMN (300 MHz, CDCl3): δ (ppm) = 7.29 (t, J =
8.2 Hz, 1H), 6.99-6.93 (m, 3H), 6.88 (ddd, J = 8.2, 2.5,
0.9 Hz, 1H), 6.12 (dt, J = 9.8, 1.9 Hz, 1H), 5.42 (dd, J =
9.8, 6.0 Hz, 1H), 3.81 (s, 3H), 2.65-2.60 (m, 2H). 13C
RMN (75 MHz, CDCl3): δ (ppm) = 164.0, 159.7, 145.2,
140.0, 129.7, 121.4, 118.2, 114.0, 111.5, 79.0, 55.3, 31.6.
HRMS (ESI): m/z [M+Na+] calcd for C12H12NaO3:
227.0679; found: 227.0670.
4.14. 6-Oxaspiro[4,5]decen-8-en-7-one (7c)35
4.18.2 Deprotection of the dioxolane / rearrangement
Brown oil. Yield: 75% (181 mg isolated from 6c (284
1
To the crude mixture obtained after irradiation (1 mmol)
dissolved in a 1:2 solution of acetonitrile and water was
added in one portion at 60°C, cerium ammonium nitrate
(1.36g, 2.5 mmol). The resulting mixture was heated at
70°C until complete disappearance of the starting
material. After cooling to r.t., the aqueous phase was
extracted with diethylether (3 x 10mL). The combined
organic layers were dried over MgSO4. After filtration and
concentration, the resulting mixture was purified by flash-
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 6.84 (dt, J =
9.8, 4.3 Hz, 1H), 6.02 (dt, J = 9.8, 1.9 Hz, 1H), 2,52 (dd, J
= 4.3, 1.9 Hz, 2H), 2.12-2.04 (m, 2H), 1.93-1.86 (m, 2H),
1.70-1.61 (m, 4H). 13C NMR (75 MHz, CDCl3): δ (ppm) =
164.6, 144.6, 121.6, 90.8, 38.9, 34.0, 23.7. HRMS (ESI):
m/z [M+Na+] calcd for C9H12NaO2: 175.0730; found:
175.0725.
4.15. 1-Oxaspiro[5,5]undecen-3-en-2-one (7d)
chromatography
AcOEt/hexanes).
over
silica
(eluent:
35/65
Brown oil. Yield: 87% (135 mg isolated from 6d (180
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 6.63 (dt, J =
1
9.8, 4.3 Hz, 1H), 6.01 (dt, J = 9.8, 2.0 Hz, 1H), 2.40 (dd, J
= 9.8, 2.0 Hz, 2H), 2.01-1.94 (m, 2H), 1.81-1.70 (m, 2H),
1.58-1.43 (m, 6H). 13C NMR (75 MHz, CDCl3): δ (ppm) =
164.0, 143.2, 121.2, 81.4, 36.5, 34.7, 25.5, 21.7. HRMS
(ESI): m/z [M+Na+] calcd for C10H14NaO2: 189.0886;
found: 189.0879.
4.19. Furofuranone (10a)
Colorless oil. Yield: 16% (23 mg isolated from 7a (122
1
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 5.95 (d, J =
4.9 Hz, 1H), 4.22 (p, J = 7.0 Hz, 1H), 3.12-3.01 (m, 1H),
2.80 (dd, J = 17.9, 8.5 Hz, 1H), 2.53-2.38 (m, 2H), 1.75-
1.64 (m, 1H), 1.57-1.21 (m, 14H), 0.87 (t, J = 6.7 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ (ppm) = 174.4, 108.8, 83.5,
40.1, 37.0, 36.8, 36.2, 32.0, 29.6, 29.6, 29.4, 26.2, 22.8,
14.2. HRMS (ESI): m/z [M+Na+] calcd for C14H24NaO3:
263.1618; found: 263.1618. IR (ATR): 1776 (C=O), 1111
(C-O) cm-1.
4.16. 1-Oxaspiro-9-t-butyl[5,5]undecen-3-en-2-one (7e)
White solid. Mp = 101-102°C. Yield: 81% (130 mg
1
isolated from 6e (180 mg)). H NMR (300 MHz, CDCl3):
δ (ppm) = 6.70 (dt, J = 9.8, 4.3 Hz, 1H), 5.93 (dt, J = 9.8,
2.2 Hz, 1H), 2,30 (dd, J = 4.4, 2.2 Hz, 2H), 2.17-2.10 (m,
2H), 1.57-1.38 (m, 4H), 1.33-1.20 (m, 2H), 1.02-0.88 (m,
1H), 0.81 (s, 9H). 13C NMR (75 MHz, CDCl3): δ (ppm) =
163.8, 143.4, 120.9, 80.2, 47.7, 36.8, 36.0, 32.4, 27.6,
21.8. HRMS (ESI): m/z [M+Na+] calcd for C14H22NaO2:
245.1512; found: 245.1516.
4.20. Furofuranone (10c)
Colorless oil. Yield: 48% (100 mg isolated from 8c (177
1
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 6.03 (d, J =
5.5 Hz, 1H), 3.18 (dddd, J = 9.9, 5.5, 4.6, 2.8 Hz, 1H),
2.84 (dd, J = 18.4, 9.9 Hz, 1H), 2.49 (dd, J = 18.4, 2.8 Hz,
1H), 2.27 (dd, J = 13.1, 9.5 Hz, 1H), 2.01-1.57 (m, 9H).
13C NMR (75 MHz, CDCl3): δ (ppm) = 175.2, 108.9, 95.3,
42.0, 39.6, 39.4, 39.3, 36.2, 24.4, 23.5. IR (CHCl3): ν (cm-
1) = 2958, 2871, 1769, 1451, 1177, 1112, 962. HRMS
(ESI): m/z [M+Na+] calcd for C10H14NaO3: 205.0835;
found: 205.0838. IR (ATR): 1770 (C=O), 1113 (C-O) cm-
4.17. 1-Oxaspiro-9-phenyl[5,5]undecen-3-en-2-one (7f)
White solid. Mp = 113-114°C. Yield: 76% (340 mg
1
isolated from 2f (500 mg)). H NMR (300 MHz, CDCl3): δ
(ppm) = 7.32-7.17 (m, 5H), 6.77 (dt, J = 9.2, 4.2 Hz, 1H),
6.02 (dt, J = 9.2, 1.9 Hz, 1H), 2.54 (tt, J = 12.3, 3.9 Hz,
1H), 2.40 (dd, J = 4.2, 1.9 Hz, 2H), 2.31-2.23 (m, 2H),
2.02 (qd, J = 13.6, 3.9 Hz, 2H), 1.76-1.70 (m, 2H), 1.52
(td, J = 13.6, 3.9 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ
(ppm) = 163.6, 146.3, 143.4, 128.3, 126.8, 126.1, 120.8,
79.7, 43.6, 36.4, 35.8, 28.3.HRMS (ESI): m/z [M+Na+]
1
.
4.21. Furofuranone (10d)
Colorless oil. Yield: 46% (57 mg isolated from 8d (153
1
mg)). H NMR (300 MHz, CDCl3): δ (ppm) = 6.00 (d, J =
+
calcd for C16H18NaO2 : 265.1199; found: 265.1205.
5.3 Hz, 1H), 3.20-3.08 (m, 1H), 2.81 (dd, J = 18.1, 8.9 Hz,
1H), 2.47 (dd, J = 18.1, 1.7 Hz, 1H), 2.18 (dd, J = 13.1,
9.9 Hz, 1H), 1.74-1.32 (m, 11H). 13C NMR (75 MHz,
CDCl3): δ (ppm) = 174.9, 109.0, 88.6, 42.1, 39.5, 39.0,
38.2, 36.8, 25.2, 23.6, 23.6. IR (CHCl3): ν (cm-1) = 2931,
4.18. Access to furofuranones – General procedure
4.18.1 Irradiation of lactone 7

7
Tetrahedron
ACCEPTED MANUSCRIPT
2856, 1762, 1418, 1129, 1122, 909. HRMS (ESI): m/z
[M+Na+] calcd for C11H16NaO3: 219.0992; found:
219.0986. IR (ATR): 1762 (C=O), 1123 (C-O) cm-1.
(6) Rosselli S, Maggio A, Piozzi F, Simmonds MSJ, Bruno M.
J. Agric. Food Chem. 2004; 52:7867-7871.
(7) Guizzinti G, Brady TP, Fischer D, Malhotra V,
Theodorakis EA. Bioorg. Med. Chem. 2010; 18:2115-
2122.
4.22. Furofuranone (10e)
White solid. Mp = 139-140°C. Yield: 48% (41 mg isolated
1
(8) Yang X-Y, Feng T, Ding J-H, Yin X, Guo H, Li Z-H, Liu
from 8e (101 mg)). H NMR (300 MHz, CDCl3): δ (ppm)
J-K. Nat. Prod. Bioprospect. 2013; 3:48-51.
= 6.02 (d, J = 5.3 Hz, 1H), 3.20-3.09 (m, 1H), 2.81 (dd, J
= 18.2, 9.0 Hz, 1H), 2.48 (dd, J = 18.2, 1.9 Hz, 1H), 2.11
(dd, J = 13.1, 9.9 Hz, 1H), 1.83 (dt, J = 9.1, 2.7 Hz, 1H),
1.74 (dt, J = 9.8, 2.9 Hz, 1H), 1.64-1.51 (m, 3H), 1.47-
1.34 (m, 4H), 1.01-0.92 (m, 1H), 0.85 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ (ppm) = 174.9, 109.2, 87.1, 47.3,
43.8, 39.2, 38.9, 38.7, 36.7, 32.5, 27.6, 23.6, 23.4. IR
(9) Yang X-Y, Feng T, Li Z-H, Yin X, Leng Y, Liu J-K. Org.
Lett. 2012; 14:5382-5384.
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47:9357-9368; (b) Trost BM, Toste, FD. J. Am. Chem.
Soc. 2003; 125:3090-3100.
(cm-1) = 2938, 2861, 1774, 1446, 1150,
(11) (a) Petit F, Furstoss R. Tetrahedron: Asymmetry 1993;
4:1341-1352; (b) Gebbinck, EA, Bouwman CT, Bourgois
M, Jansen BJM, de Groot A. Tetrahedron 1999; 55:11051-
11076 ; (c) Donate PM, da Silva R, da Silva GVJ, Aleman
C. Synth. Commun. 2001; 31:141-150 ; (d) Malanga C,
Mannucci S, Lardicci L. J. Chem. Research (S), 2001; 97-
99; (e) Alonso F, Rodriguez-Fernandez M, Sanchez D,
Yus M. Synthesis 2010; 3013-3020; (f) Schnermann M J,
Beaudry CM, Genung NE, Canham SM, Untiedt NL,
Karanikolas BDW, Sütterlin C, Overman LE. J. Am.
Chem. Soc. 2011; 133:17494-17503; (g) Sridhar PR,
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Chem. Front. 2007; 4:2358-2363.
(CHCl3) : ν
1104, 928. HRMS (ESI): m/z [M+Na+] calcd for
C15H24NaO3: 275.1618; found: 275.1611. IR (ATR): 1774
(C=O), 1105 (C-O) cm-1.
4.23. Furofuranone (10f)
White solid. Mp = 151-152°C. Yield: 40% (112 mg
isolated from 8f (251 mg)).1H NMR (300 MHz, CDCl3): δ
(ppm) = 7.31-7.15 (m, 5H), 6.05 (d, J = 5.3 Hz, 1H), 3.23-
3.12 (m, 1H), 2.82 (dd, J = 18.1, 9.0 Hz, 1H), 2.53-2.44
(m, 2H), 2.19 (dd, J = 13.3, 9.7 Hz, 1H), 2.03-1.68 (m,
6H), 1.65-1.50 (m, 3H). 13C NMR (75 MHz, CDCl3): δ
(ppm) = 174.7, 146.9, 128.5, 127.0, 126.2, 109.1, 86.7,
43.9, 43.4, 39.3, 38.7, 38.5, 36.7, 30.2, 30.2. IR (CHCl3):
ν (cm-1) = 2935, 2875, 1757, 1413, 1196 1115, 950.
HRMS (ESI): m/z [M+Na+] calcd for C17H20NaO3:
295.1305; found: 295.1310. IR (ATR): 1757 (C=O), 1114
(C-O) cm-1.
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Acknowledgement
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M. J. Org. Chem. 1998; 63:5895-5902; (b) Fehring V,
Knights S, Chan M-Y, O’Neil IA, Cosstick R. Org.
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KA, Kim M-W. Tetrahedron 2011; 67:837-841.
L.R. and Y.N. both thank the Ministère de la Recherche et
de l’Enseignement Supérieur for a Ph-D grant. S.V. thanks
the E.U. Erasmus program exchange. Financial supports
from Université de Lyon, Institut de Chimie de Lyon (ICL)
and CNRS are also warmly acknowledged.
(14) Enders D, Vazquez J, Raabe G. Eur. J. Org. Chem. 2000,
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