Synthesis of 3-oxo oxacycloalkenes by ring closing metathesis

Article abstract of DOI:10.1016/S0040-4039(02)01544-7

The synthesis of six-, seven- and eight-membered 3-oxo oxacycloalkenes by using ring-closing metathesis has been achieved from 1-(ω-alkenyloxy)-but-3-en-2-ones.

Full text of DOI:10.1016/S0040-4039(02)01544-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7263–7266
Synthesis of 3-oxo oxacycloalkenes by ring closing metathesis
Janine Cossy,* Catherine Taillier and Ve´ronique Bellosta
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 17 July 2002; accepted 25 July 2002
Abstract—The synthesis of six-, seven- and eight-membered 3-oxo oxacycloalkenes by using ring-closing metathesis has been
achieved from 1-(v-alkenyloxy)-but-3-en-2-ones. © 2002 Elsevier Science Ltd. All rights reserved.
Cyclic ether-containing natural and non-natural prod-
ucts represent architecturally challenging and biologi-
cally important molecules1,2 that have stimulated the
development of an array of methods for their synthe-
sis.3 The number of methods available for the construc-
tion of cyclic ethers has steadily increased and among
them, ring closing metathesis has proven to be
efficient.3e,4 The aim of this study was to identify a
general strategy for the synthesis of functionalized
3-oxo oxacyclic compounds of type A as these com-
pounds can be the precursors of cyclic skeleton of a
large number of natural products (Scheme 1).2
Although very few examples of ring-closing metathesis
(RCM) reactions involving conjugated ketones were
reported,5 we have decided to examine the reactivity of
1-(v-alkenyloxy)-but-3-en-ones in the metathesis pro-
cess for obtaining six-, seven- and eight-membered 3-
oxo oxacycloalkenes. Thus, we required a general route
to synthesize a broad range of acyclic a-alkoxy enones
of type B (Scheme 1).
and tertiary alcohols by using the previous sequence as
the coupling reaction of the acyl chlorides with the
tri-n-butylvinyltin did not lead to the desired a-alkoxy
enones of type B but to decomposed products. Thus,
a-alkoxy enones of type B were prepared via the stabi-
lized phosphoranes 15–19 (Scheme 3). These latter com-
pounds were obtained by alkylation of the secondary
and tertiary alcohols 10–14 by using sodium hydride (4
equiv.) with triphenylchloroacetonylphosphorane in
THF in yields greater than 48%.7 The obtained phos-
phoranes 15–19 were converted, respectively, to the
a-alkoxy enones 20–24 in more than 50% yield by
condensation with formaldehyde (Table 2).7,8 It is
worth noting that the access to linear a-alkoxy enones
7–9 also proved to be effective by using this
methodology.
The synthesis of compounds of type B, when R=R%=
H, has been accomplished by condensing v-unsaturated
alcohols 1–3 with chloroacetic acid under basic condi-
tions (NaH, 2.2 equiv.) in THF at rt (Scheme 2). The
corresponding a-alkoxy acetic acids 4–6 were obtained
in yields greater than 50%. The transformation of the
acids to a-alkoxy enones 7–9 was achieved in two steps
via the acyl chlorides 4–6 [(COCl)2, cat. DMF, benzene,
rt, 1 h] which were then treated with tri-n-butylvinyltin
in the presence of Pd(PPh3)2BnCl (0.4 mol%) in HMPA
(60°C, 45 min)6 to afford the desired a-alkoxy enones
7–9 in yields greater than 35% (Table 1).
Scheme 1.
Compounds of type B, where R=alkyl or aryl and
R%=H or alkyl, could not be obtained from secondary
* Corresponding author. Fax: +33-1-40-79-46-60; e-mail: janine.cossy
@espci.fr
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01544-7

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J. Cossy et al. / Tetrahedron Letters 43 (2002) 7263–7266
a-Alkoxy acetic acid
Table 1.
Entry
Alcohol
a-Alkoxy enone
Yield (%)
1–3
Product
Yield (%)
Product
1
2
3
1 (n=0)
2 (n=1)
3 (n=2)
4
5
6
70
56
51
7
8
9
37
58
51
Cl
The other substrates 7, 9, 20–24 were examined in the
RCM reaction and the results are reported in Table
3. All the reactions were carried out with 2.5 to 10
mol% of Grubbs’ catalyst II, at the indicated concen-
trations in refluxing dichloromethane (Scheme 5). In
general, it was found that the RCM provided the
cyclic compounds in good yields irrespective of the
substitution pattern present in the substrates. In gen-
eral, eight-membered rings are difficult to obtain by
using RCM and we were particularly gratified that
a-alkoxy enones 9 and 24 were equally effective sub-
strates in the RCM as 31 and 32 were formed (Table
3, entries 8 and 9), even at a concentration of 10−2
M.12
O
R' R
R' R
OH
Ph3P
NaH
O
PPh3
n
n
O
n= 0, 1, 2
THF
10-14
15-19
rt or reflux
CH2O
R' R
H2O/Et2O, rt
O
n
O
20-24
Scheme 3.
The above metathesis products are well-suited for fur-
ther manipulations. To demonstrate this point, com-
pound 29 was subjected to a dihydroxylation reaction
(OsO4 cat., NMO, acetone/H2O) and diol 33 was iso-
lated in 80% yield with a diastereomeric ratio of 95/5.
Osmylation presumably occurs on the less hindered
face anti to the phenyl group (Scheme 6).
With the required 1-(v-alkenyloxy)-but-3-en-2-ones in
hand, we set out to investigate the ring-closing
metathesis of these compounds. The initial tests were
conducted on a-alkoxy enone 8. With Grubbs’ cata-
lyst I (Scheme 4),9 the formation of the cyclic enone
was not observed in the absence or in the presence of
Ti(Oi-Pr)4.5c,10 However, when 8 was treated with 15
mol% of Grubbs’ catalyst II (Scheme 4) in refluxing
dichloromethane,11 the starting material was trans-
formed to the cyclic enone 27 in 58% yield (Table 3,
entry 3). It was found that 2.5 mol% of catalyst II
was sufficient to provide 27 in 42% isolated yield
(Table 3, entry 4).
To gain entrance to natural products, selective alkyla-
tions on 29 were also achieved (Scheme 7). When 29
was subjected to lithium dimethylcuprate, compound
34 was obtained in 60% yield with a diastereomeric
ratio of 86/14,13 and when 29 was treated with LDA
in HMPA/THF followed by the addition of methyl
iodide at −78°C the monomethylated product 35 was
obtained in 48% yield, as a single isomer.14
In conclusion, we have shown that 1-(v-alkenyloxy)-
but-3-en-2-ones can readily undergo RCM reaction
affording six-, seven- and even eight-membered 3-oxo
oxacycloalkenes in good yields. The use of this
methodology is currently being investigated in our
laboratory for the synthesis of natural products.
Scheme 4.
Table 2.
Entry
Alcohol
Conditions
Temp. (°C)
Phosphorane
Yield (%)
a-Alkoxy enone
10–14
Time (h)
Product
Product
Yield (%)
1
2
3
4
5
10 (n=0, R=H, R%=i-Pr)
11 (n=1, R=H, R%=i-Pr)
12 (n=1, R=H, R%=Ph)
13 (n=1, R=R%=Me)
5
7
12
1
70
20
20
70
70
15
16
17
18
19
94
48
70
82
76
20
21
22
23
24
67
49
73
49
54
14 (n=2, R=H, R%=i-Pr)
6

J. Cossy et al. / Tetrahedron Letters 43 (2002) 7263–7266
7265
R' R
O
n
Grubbs' cat. II
O
R'
n
CH2Cl2, 50 °C, 12h
O
O
R
n= 0, 1, 2
7-9, 20-24
25-32
Scheme 5.
HO
OH
O
O
OsO4 cat, NMO
H2O/acetone, rt, 3h
80%
O
O
Scheme 7.
Ph
Ph
29
33
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1
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1
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