Straightforward synthesis of 1,7-dioxaspiro[4.4]nonanes

Article abstract of DOI:10.1016/j.tetlet.2003.12.094

The reaction of 2-chloromethyl-3-(2-methoxyethoxy)prop-1-ene with an excess of lithium powder and a catalytic amount of naphthalene (2.5%) in the presence of a carbonyl compound (E¹=R¹R²CO) in THF at -78 to 0°C, followed by the addition of an epoxide [E ²=R³R⁴C(O)CHR⁵] at 0 to 20deg;C leads, after hydrolysis, to the expected methylidenic diols. These diols, in the presence of iodine and silver(I) oxide in dioxane-water, undergo double intramolecular iodoetherification to give the corresponding 1,7-dioxaspiro[4.4] nonanes, which in addition can be easily oxidised to a variety of 1,7-dioxaspiro[4.4]nonan-6-ones.

Full text of DOI:10.1016/j.tetlet.2003.12.094

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1717–1720
Straightforward synthesis of 1,7-dioxaspiro[4.4]nonanes
*
ꢀ
Francisco Alonso, Jaisiel Melendez and Miguel Yus
ꢀ
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Facultad de Ciencias, and Instituto de Sıntesis Organica (ISO), Universidad de Alicante,
Apdo. 99, E-03080-Alicante, Spain
Received 4 December 2003; accepted 16 December 2003
Abstract—The reaction of 2-chloromethyl-3-(2-methoxyethoxy)prop-1-ene with an excess of lithium powder and a catalytic amount
of naphthalene (2.5%) in the presence of a carbonyl compound (E1 ¼ R1R2CO) in THF at )78 to 0 °C, followed by the addition of
an epoxide [E2 ¼ R3R4C(O)CHR5] at 0 to 20 °C leads, after hydrolysis, to the expected methylidenic diols. These diols, in the
presence of iodine and silver(I) oxide in dioxane–water, undergo double intramolecular iodoetherification to give the corresponding
1,7-dioxaspiro[4.4]nonanes, which in addition can be easily oxidised to a variety of 1,7-dioxaspiro[4.4]nonan-6-ones.
Ó 2003 Elsevier Ltd. All rights reserved.
The 1,7-dioxaspiro[4.4]nonane skeleton and its derived
lactones are present in a wide and diverse series of
natural products, some of them with important biolog-
ical activities. This type of compounds are especially
abundant within the family of the labdane diterpenoids,
two representatives of which are prehispanolone (I)
(a specific platelet activating factor receptor antagonist,
isolated from the Chinese herbal medicine Leonurus
heterophyllus)1;2 and leopersin J (II) (from Leonurus
persicus).3 Some other naturally occurring compounds
containing the mentioned substructure are sphydrofuran
(III) (a secondary metabolite produced by Actinomy-
cetes),4 cinatrin A (IV) (a potent inhibitor of rat platelet
phospholipase A2, from the fermentation broth of the
microorganism Circinotrichum falcatisporum),5 longia-
none (V) (from Xylaria longiana),6 or hyperolactone A
(VI) (from Hypericum chinense L.).7 1,7-Dioxa-
spiro[4.4]nonanes have also been used as valuable
polycyclic scaffolds in the synthesis of natural products
(e.g., VII, in zaragozic acid synthesis)8 or have been
obtained as a result of carbohydrate modification
(VIII)9 (Chart 1).
able methodologies have focussed on the synthesis of
spirocyclic c-mono- and bislactones, less attention being
dedicated to the 1,7-dioxaspiro[4.4]nonane itself as a
polycyclic ether. These methodologies normally involve
the intramolecular cyclisation of a moiety attached to a
preformed c-lactone or tetrahydrofuran ring. As repre-
sentative examples we can mention: (a) the intramolec-
ular Michael addition of a 3-hydroxyalkyl group to a
2-butenolide ring;10 (b) Reformatsky-type reaction on a
tetrahydrofuran-3-one, followed by lactonisation;11 (c)
lactonisation of 2-hydroxyalkyl-c-lactone acids;12 (d)
radical cyclisation of a 4-(3-butynyloxy)-2,5-dihydro-2-
furanone;13 or (e) intramolecular ketalisation from a 2,2-
disubstituted tetrahydrofuran.14
On the other hand, in the recent years we have shown an
increasing interest in the synthesis of bicyclic15–19 and
spirocyclic20;21 polyether skeletons as constituents of
important biologically active compounds. In particular,
and in connection withthe title topic, we reported the two-
step synthesis of 1,6-dioxaspiro[3.4]octanes from
3-chloro-2-(chloromethyl)prop-1-ene20 and 1,5-dioxa-
spiro[2.4]heptanes from 2,3-dichloroprop-1-ene.21 In
both cases an arene-catalysed lithiation22–24 under Barbier
conditions25;26 and an iodine-mediated double intramo-
lecular cyclisation were utilised as the key reaction steps.
Due to the unique structural nature of these spirocyclic
compounds, their syntheses represent a major challenge
for the organic chemist.10 However, most of the avail-
We want to describe herein a methodology that allows a
straight and ready access to the title compounds, using
2-chloromethyl-3-(2-methoxyethoxy)prop-1-ene (1) as
starting material. This compound underwent a selective
naphthalene-catalysed lithiation with concomitant one-
pot incorporation of two different electrophilic fragments,
Keywords: 1,7-Dioxaspiro[4.4]nonanes; Arene-catalysed lithiation;
Spirolactones; Spirocyclisation.
* Corresponding author. Tel.: +34-965903548; fax: +34-965903549;
e-mail: yus@ua.es
URL: http://www.ua.es/dept.quimorg/
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.094

1718
F. Alonso et al. / Tetrahedron Letters 45 (2004) 1717–1720
OH
OH
O
OH
CO2H
HO
O
O
HO
O
O
8
O
O
O
HO
Me
O
O
O
O
H
H
cinatrin A (IV)
sphydrofuran (III)
OH
prehispanolone (I)
leopersin J (II)
O
N3
O
O
O
O
BnO
O
O
O
O
TBDPSO
O
O
O
CO2Me
BnO
OBn
(VIII)
OTMS
O
O
longianone (V)
(VII)
hyperolactone A (VI)
Chart 1.
derived from a carbonyl compound and an epoxide,
respectively.19 The resulting methylidenic diols (2) were
regioselectively cyclised in the presence of iodine and
silver(I) oxide, affording the expected 1,7-dioxa-
spiro[4.4]nonanes (3) in high yields. In addition, these
compounds could be easily oxidised to the correspond-
ing 1,7-dioxaspiro[4.4]nonan-6-ones (5).
higher temperature) and subsequent reaction with the
epoxide.19
The isolated diols (2) were treated with iodine (1.5 equiv)
and silver(I) oxide (1.5 equiv) in a 7:1 mixture of diox-
ane–water at room temperature overnight, to give the
corresponding 1,7-dioxaspiro[4.4]nonanes 3 in excellent
yields and with high purity (Scheme 1 and Table 1). In
particular, compounds 3e–h are polyspirocyclic mole-
cules especially interesting from the structural point of
view. It is worth of note that chiral racemic diols were
obtained when 1-octene, styrene and cyclohexene oxides
were used as second electrophiles (Table 1, compounds
2c,d,h), and consequently some asymmetric induction
could be expected in the formation of the new spiro-
cyclic stereocentre. Spirocyclisation of diol 2d gave a
disappointing 1:1 diastereomeric ratio, whereas a 3.5:1
ratio was observed for diol 2c. However, the cyclisation
of diol 2h led to an interesting 12:1 mixture of diaste-
reoisomers (85% de) in favour of 3h, the structure of
which was confirmed by a NOESY experiment. This
result can be promising in the synthesis of chiral non-
racemic 1,7-dioxaspiro[4.4]nonanes by utilising enan-
tiomerically pure epoxides as second electrophiles.
The reaction of 2-chloromethyl-3-(2-methoxyeth-
oxy)prop-1-ene (1) with an excess of lithium powder (1:7
molar ratio) and a catalytic amount of naphthalene
(1:0.1 molar ratio, 2.5 mol %), in the presence of different
carbonyl compounds (E1 ¼ R1R2CO; 1:0.95 molar ratio)
in THF, at temperatures ranging from )78 to 0 °C for
ca. 3.5 h, led to a reaction mixture, which was treated
with an excess of an epoxide as a second electrophile
[E2 ¼ R3R4C(O)CHR5; 1:3 molar ratio] at 0 to 20 °C
overnight giving, after hydrolysis with water, the cor-
responding methylidenic diols 2a–h (Scheme 1 and
Table 1). Among them, those symmetrically substituted
were readily obtained using a ketone as the first elec-
trophile and the epoxide derived from that ketone as the
second electrophile (Table 1, compounds 2f,g). In the
case of using cyclohexene oxide as the second electro-
phile, only the corresponding trans-diastereomer was
obtained (Table 1, compound 2h).
It must be mentioned that spirocyclisation of the diol 2f
could not be driven to completion, what explained the
lower yield observed in the formation of 3f (70%)
compared to the rest of compounds 3. However, this
reaction allowed the isolation of the corresponding
iodohydrin intermediate 4f (15%). From this compound
it can be inferred that the first cyclisation involves the
epoxide derived moiety, followed by final intramolecular
iodoetherification. Therefore, this mode of cyclisation
This sequential incorporation of two electrophilic frag-
ments arises from the different reactivity of the carbon–
chlorine and carbon–oxygen bonds in arene-catalysed
lithiations. Thus, the whole process is suggested to take
place through an initial chlorine–lithium exchange with
concomitant addition to the carbonyl compound, fol-
lowed by an allylic carbon–oxygen bond cleavage (at
R4
R3
R5
OH
R2
R1
R2
MeO
R1
OH
i-iii
iv
O
O
Cl
R4
R3
O
R5
1
2
3
Scheme 1. Reagents and conditions: i, Li, C10H8 (2.5 mol %), R1R2CO, THF, )78 to 0 °C, 3.5 h; ii, R3R4C(O)CHR5, 0 to 20 °C, overnight; iii, H2O;
iv, I2, Ag2O, dioxane–H2O (7:1), 20 °C, overnight.

F. Alonso et al. / Tetrahedron Letters 45 (2004) 1717–1720
Table 1. Obtention of 1,7-dioxaspiro[4,4]nonanes 3 from diols 2
1719
Product 2a
Product 3a
No.
Structure
Yield (%)b
No.
Structure
Yield (%)c
98
OH
O
2a
2b
70
3a
3b
O
OH
OH
n-C5H11
n-C5H11
O
n-C5H11
43
96
O
n-C5H11
OH
OH
OH
n-C6H13
O
2c
2d
55
68
3c
3d
97d
88e
n-C6H13
OH
O
Ph
O
Ph
O
OH
OH
2e
2f
41
33
3e
3f
96
O
OH
O
OH
70f
O
OH
O
OH
O
2g
2h
54
43
3g
3h
92
OH
O
OH
H
H
93g
O
OH
O
a All products were P 95% pure (GLC and/or 300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C NMR, and
MS).
b Isolated yield after column chromatography (silica gel, hexane/EtOAc) based on the starting chloroether 1.
c Yield of pure 3 from the reaction crude (unless otherwise is stated) based on the starting diol 2.
d Obtained as a 3.5:1 mixture of diastereoisomers.
e Obtained as a 1:1 mixture of diastereoisomers.
f Isolated yield after column chromatography (silica gel, hexane/EtOAc) based on the corresponding diol 2f.
g Obtained as a 12:1 mixture of diastereoisomers (85% de), the major diastereoisomer is shown.
leading regioselectively to the 1,7-dioxaspiro[4.4]non-
anes is more favoured than the alternative one leading to
the 1,6-dioxaspiro[3.5]nonanes (see IX).
derived lactones. We believed that the spirocyclic
compounds synthesised 3 could be used as adequate
precursors of 1,7-dioxaspiro[4.4]nonan-6-ones by oxi-
dation adjacent to the tetrahydrofuran oxygen atom.
Among the different methods available to carry out this
transformation, the system composed of catalytic
ruthenium(IV) oxide and sodium periodate gave excel-
lent results (for some applications of this oxidation
system, see for instance Ref. 27). Thus, by treating the
1,7-dioxaspiro[4.4]nonanes 3a,c,e,g with a catalytic
amount (0.15 equiv) of RuO2 and an excess of NaIO4
(4.88 equiv), in CCl4–H2O (1:1) at room temperature,
the corresponding lactones 5a,c,e,g were obtained,
respectively, in remarkable yields and without any fur-
ther purification (Chart 2).
H
O
O
+
O
H
OH
I
I
4f
IX
As shown Chart 1, not only 1,7-dioxaspiro[4.4]nonanes
themselves are interesting compounds but also the

1720
F. Alonso et al. / Tetrahedron Letters 45 (2004) 1717–1720
n-C6H13
O
O
O
O
O
O
O
O
O
O
O
O
5a (98%)
5c (95%)
5g (91%)
5e (97%)
Chart 2.
10. For a review, see: Wong, H. N. C. Eur. J. Org. Chem.
1999, 1757–1765.
Acknowledgements
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ꢀ
This work was generously supported by the Direccion
General de Ensenanza Superior (DGES) of the Spanish
~
ꢀ
Ministerio de Educacion, Cultura y Deporte (MECD;
€€
12. Paju, A.; Kanger, T.; Pehk, T.; Lindmaa, R.; Muurisepp,
grant no. BQU2001-0538) and the Generalitat Valenci-
ana (GV; grant no. CTIDIB/2002/318). J.M. thanks the
Generalitat Valenciana for a predoctoral grant.
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