Synthesis and reactivity of 1-hydroxyspiro[2.5]cyclooct-4-en-3-ones

Article abstract of DOI:10.1016/j.tetlet.2004.03.134

The first 1-hydroxyspiro[2.5]cyclooct-4-en-3-ones were prepared by cyclization of free and masked 1,3-dicarbonyl dianions with 1,1- diacetylcyclopropane. 1-Hydroxyspiro[2.5]cyclooct-4-en-3-ones represent precursors of unstable spiro[5.2]cycloocta-4,7-dien-6-ones and reactions with a number of nucleophiles were studied. The reactions are enhanced by dynamic spiro-activation.

Full text of DOI:10.1016/j.tetlet.2004.03.134

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3861–3863
Synthesis and reactivity of 1-hydroxyspiro[2.5]cyclooct-4-en-3-ones
Gopal Bose and Peter Langer*
Institut f €u r Chemie und Biochemie der Ernst-Moritz-Arndt Universit €a t Greifswald, Soldmannstr. 16, D-17487 Greifswald, Germany
Received 17 March 2004; accepted 22 March 2004
Abstract—The first 1-hydroxyspiro[2.5]cyclooct-4-en-3-ones were prepared by cyclization of free and masked 1,3-dicarbonyl dia-
nions with 1,1-diacetylcyclopropane. 1-Hydroxyspiro[2.5]cyclooct-4-en-3-ones represent precursors of unstable spiro[5.2]cycloocta-
4
ꢀ
,7-dien-6-ones and reactions with a number of nucleophiles were studied. The reactions are enhanced bydynamic spiro-activation.
2004 Elsevier Ltd. All rights reserved.
Acceptor substituted cyclopropanes represent important
building blocks in homo Michael reactions with various
nucleophiles. In this context, spiro[2.5]cycloocta-4,7-
dien-6-ones are of considerable interest; theycan be
regarded as vinylogous ketone substituted cyclopro-
panes. The rather unstable parent compound has been
We have recentlyreported the TiCl 4 mediated cycliza-
tion of 1,3-bis-silyl enol ethers with 1,1-diacetylcyclo-
1;2
7
propane. This reaction proceeds byTiCl
cyclization, subsequent TiCl mediated cyclopropylcar-
4
mediated
4
binyl fi homoallyl rearrangement to give phenols with
chlorinated side chain. Herein we report the synthesis of
1-hydroxyspiro[2.5]cyclooct-4-en-3-ones by cyclization
of free and masked 1,3-dicarbonyl dianions with
1,1-diacetylcyclopropane. Thereactionof1-hydroxyspiro-
[2.5]cyclooct-4-en-3-ones, which represent stable pre-
cursors of (unstable) acceptor-substituted spiro[2.5]cy-
cloocta-4,7-dien-6-ones, with a varietyof nucleophiles
was studied. The products, functionalized salicylates,
are of considerable pharmacological relevance and occur in
a varietyof natural products and their analogues (e.g.,
salicylic acids, esters and glycosides) and in synthetic
3
b;4c
previouslyprepared, however, in only2–4% yi eld.
ꢀ
3
In contrast, ether solutions (10 M) proved to be
more stable and reactions with HBr, LiAlH or NaOMe
have been reported to give phenols. A number of
substituted spiro[2.5]cycloocta-4,7-dien-6-one have been
which have been used for photochemical,
electrochemical and other transformations. This in-
cludes mainlykineticallystabilized, stericallyhindered
4
3
4a;b
4c
reported,
4d
4c;d;5
compounds.
Derivatives with aromatic rings fused
to the double bonds represent an interesting subclass of
spiro[2.5]cycloocta-4,7-dien-6-ones, which have been
used during the synthesis of natural products, such as
ꢀ
8
drugs (e.g., aspirin ). These products are mostlynot
available by direct cyclization of bis-silyl enol ethers
with 1,1-diacylcyclopropanes. The work reported herein
6
CC-1065 or duocarmycin SA. In fact, the spiro[2.5]cy-
cloocta-4,7-dien-6-one moietypla ys an important role
for the strong antitumour activityof these compounds.
offers
a
convenient approach to functionalized
spiro[2.5]cyclooct-4-en-3-ones and represents a signifi-
cant extension of known syntheses of functionalized
salicylates.
OMe
OMe
The cyclization of the dianions of methyl acetoacetate
9
N
and acetylacetone, generated by LDA, with 1,1-di-
10
N
OMe
MeO2C
H
acetylcyclopropane (3)
afforded the 1-hydroxy-
O
N
H
spiro[5.2]cyclooct-4-en-3-ones 4b and 4d, respectively.
During the optimization, the use of an excess of the
dianion (2 equiv) proved to be an important parameter.
The application of 1,3-bis-silyl enol ethers 2, which can
O
Duocarmyin SA
1
1;12
be regarded as masked dianions,
The cyclization of 2a with 3 in the presence of TiCl4
0.3–0.5 equiv) allowed the synthesis of 1-hydroxy-
was studied next.
Keywords: Cyclizations; Cyclopropanes; Domino reactions; Spiro
compounds; Silyl enol ethers.
(
13
*
Corresponding author. Tel./fax: +49-3834-864461; e-mail: peter.
langer@uni-greifswald.de
spiro[5.2]cyclooct-4-en-3-one 4a in 50% yield. The use
of more than 0.5 equiv of TiCl resulted in cleavage of
4
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.134

3862
G. Bose, P. Langer / Tetrahedron Letters 45 (2004) 3861–3863
the cyclopropane moiety and formation of salicylate 5d
vide infra). The yield significantly decreased when less
than 0.3 equiv of TiCl or a different Lewis acid was
OH
O
O
O
(
R1
R1
conditions
4
HO
employed. Spiro[5.2]cyclooctenones 4b and 4c were
prepared in 55% and 57% yield, respectively. The acet-
ylacetone derived product 4d was obtained in 15% yield.
Our preliminaryresults show that the use of dianions is
particularlyuseful for 1,3-diketones whereas the use of
bis-silyl enol ethers are more suitable for b-ketoesters
R2
4
a-c
5a-o
Scheme 3. Synthesis of functionalized salicylates 5.
(
Scheme 1).
Table 1. Reactions of spiro[5.2]cyclooctenones 4
1
2
2
a
Treatment of 4a with trifluoroacetic acid (TFA) resulted
5
R
R
Conditions
TFA, CH Cl
TiF , CH Cl
2
% (5)
14
in formation of the trifluoroacetate 5a. The formation
of 5a can be explained byelimination of water to give a
spiro[2.5]cycloocta-4,7-dien-6-one, followed by attack of
TFA onto the cyclopropane moiety (Scheme 2). Despite
the poor nucleophilicityof TFA, 5a was isolated in 95%
yield. All attempts to directly prepare 5a byTFA-med-
iated cyclization of 2a with 3 were unsuccessful and
resulted in the formation of complex mixtures.
a
b
c
OiPr
OMe
OEt
O
F
F
CCF
3
2
2
95
26
0
4
2
Bu
BF
TiCl
Bu
BF
TiBr
Bu NBr, CH
4
NF, CH
2
Cl
2
,
3
ÆOEt
2
d
e
OiPr
OEt
Cl
Cl
4
, CH
2
Cl
2
53
84
4
NCl, CH
ÆOEt
2
Cl
2
,
3
2
f
f
OEt
OEt
Br
Br
4
94
96
4
2 2
Cl ,
BF
TiI
3
ÆOEt
, CH
2
The reaction of 1-hydroxyspiro[2.5]cyclooct-4-en-3-ones
4
g
h
OiPr
OMe
I
I
4
2
Cl
Cl
2
47
96
with other nucleophiles was studied (Scheme 3, Table
). Treatment of a CH Cl solution of 4b with TiF
afforded the fluoride 5b. Likewise, treatment of 4a with
Et
4
NI, CH
2
2
,
1
2
2
4
BF ÆOEt
3
2
i
j
OEt
OEt
OTos
OAc
TsOH, CH
AcOH, CH
BF ÆOEt
SO
2
Cl
Cl
2
61
79
TiCl afforded the chloride 5d in moderate yield. The
4
reaction of 4c and 4a with TiBr and TiI afforded the
4 4
2
2
,
3
2
k
l
OMe
OiPr
OMe
OH
H
2
4
, MeOH
40
61
57
halides 5f and 5h, respectively. The chlorination of 4c
with Bu NCl in the presence of calalytic amount of
OEt
OPh
BF
3
2
ÆOEt , EtOH
4
m
PhOH, TFA,
CH Cl
PhSH, TFA
BF
reaction of 4c and 4b with Bu
f and 5h in high yields, respectively. The reaction of 4c
with Bu NF in presence of BF ÆOEt , however, failed to
give the desired product 5c. Treatment of a CH Cl
solution of 4c with p-toluenesulfonic acid (TsOH)
3
ÆOEt
2
afforded 5e in verygood yi eld. Likewise, the
2
2
4
NBr and Bu NI afforded
4
n
o
OiPr
OEt
SPh
CH@CH
70
33
5
2
BrMgCH@CH
THF, BF
CH Cl
2
,
,
4
3
2
3 2
ÆOEt
2
2
2
2
a
Yield of isolated product.
O
O
OLi OLi
afforded the tosylate 5i. The reaction of 4c with glacial
acetic acid (AcOH) afforded the acetate 5j. The addition
of BF ÆOEt was required, presumablydue to the rela-
tivelylow acidityof AcOH. The reaction of a methanol
solution of 4b with sulfuric acid afforded the alcohol 5k
rather than the expected methyl ether. In contrast, the
ethyl ether 5l was obtained byreaction of 4a with eth-
+
O
O
i
R
3
2
R
1
3
3
HO
Me3SiO OSiMe3
ii
+
R
4a-d
2
anol in the presence of BF
the latter byTFA resulted in formation of 5l, however,
3
2
ÆOEt . The replacement of
Scheme 1. Synthesis of 1-hydroxyspiro[2.5]cyclooct-4-en-3-ones; (i) 1
in low yield. In contrast, the TFA-mediated reaction of
4
(
2 equiv), 3 (1 equiv), THF, ꢀ78 fi 20 °C, 12 h, 20 °C, 12 h, yields: 4b
R ¼ OMe): 16%, 4d (R ¼ Me): 36%; (ii) TiCl (0.3 equiv), CH Cl
b with hydroxybenzene gave the ether 5m. Likewise,
the TFA-mediated reaction of 4a with thiohydroxy-
benzene afforded the sulfide 5n. The BF ÆOEt mediated
(
4
2
2
,
ꢀ
molecular sieves (4 A), ꢀ78 fi 20 °C, 12 h, yields: 4a (R ¼ OiPr): 50%,
b (R ¼ OMe): 55%, 4c (R ¼ OEt): 57%, 4d (R ¼ Me): 15%.
4
3
2
H+
O
O
O
O
OH O
OiPr
i
OiPr
OiPr
CF3
HO
O
O
F3C
OH
O
4
a
5a (95%)
TFA
Scheme 2. Reaction of 4a with TFA; (i) TFA, CH
2
Cl
2
, 20 °C, 4 h.

G. Bose, P. Langer / Tetrahedron Letters 45 (2004) 3861–3863
3863
reaction of 4c with vinyl magnesium bromide afforded
o.
10. The starting materials were prepared according to a
known procedure: Zefirov, N. S.; Kuznetsova, T. S.;
Kozhushkov, S. I.; Surmina, L. S.; Rakina, Z. A. Zh. Org.
Khim. 1983, 19, 541.
5
Reactions of acceptor substituted cyclopropanes have
been discussed byDanishefskyin terms of ‘strictly
nucleophilic ring openings’, ‘electrophilicallyassisted
1
1. (a) Chan, T.-H.; Brownbridge, P. J. Chem. Soc.,
Chem. Commun. 1979, 578; (b) Chan, T.-H.; Brown-
bridge, P. J. Am. Chem. Soc. 1980, 102, 3534; (c)
Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc.
2
ring openings’ and ‘spiro-activation’. According to
Zefirov et al. the reactions reported herein can be
classified as being enhanced by‘d yn amic spiro-activa-
15
1993, 115, 830.
12. For a review of 1,3-bis-silyl enol ethers, see: Langer, P.
Synthesis 2002, 441.
15
tion’, which allows a rationale of the unusually mild
cyclopropane ring opening.
13. Synthesis of 4b: TiCl
.45 mmol) was added dropwise at ꢀ78 °C under argon
atmosphere to a stirred solution of 3 (0.190 g, 1.5 mmol)
and 2b (0.580 g, 2.2 mmol) in CH Cl (100 mL) in the
4
2 2
(0.05 mL in 1 mL CH Cl ,
0
2
2
ꢀ
presence of molecular sieves (4 A; 1.0 g). The reaction
mixture was allowed to warm to 20 °C over 6 h, was stirred
for additional 6 h at 20 °C and was then filtered. The
filtrate was poured into an aqueous solution of HCl
Acknowledgements
We thank Sunanda Lahiri for an experimental contri-
bution. Financial support bythe Deutsche Forschungs-
gemeinschaft is gratefullyacknowledged.
(
1.0 M, 100 mL). The organic layer was collected, and the
aqueous was extracted with CH Cl
(3 · 100 mL). The
combined organic layers were dried over anhydrous
Na SO , filtered and concentrated in vacuo. The residue
2
2
2
4
was purified bycolumn chromatography(silica gel,
hexane–ethylacetate ¼ 1:4 fi 1:1) to give 4b (0.186 g, 55%)
References and notes
as a colourless solid; mp 108–109 °C; R
f
¼ 0:13 (ethylac-
3
1
1
. (a) Houben-Weyl In Carbocyclic Three-Membered Ring
Compounds, 4th ed.; de Meijere, A., Ed.; Methoden der
Organischen Chemie; Thieme: Stuttgart, 1996; Vol. E17;
(b) The Chemistry of the Cyclopropyl Group; Rappoport,
Z., Ed.; Wiley: Chichester, 1987.
. Danishefsky, S. J. Acc. Chem. Res. 1979, 66.
. (a) Baird, R.; Winstein, S. J. Am. Chem. Soc. 1957, 79,
238; (b) Baird, R.; Winstein, S. J. Am. Chem. Soc. 1963,
5, 574.
. (a) Woolhouse, A. D. Aust. J. Chem. 1977, 30, 1145; (b)
Schuster, D. I.; Polowczyk, C. J. J. Am. Chem. Soc. 1966,
etate–hexane 1:4); H NMR (300 MHz, CDCl
(s, 3H, CH ), 2.62 (d, 1H,
), 2.72 (d, 1H, J ¼ 15:6 Hz, CH
J ¼ 15:6 Hz, CH ), 2.24 (s, 1H, OH), 1.69 (s, 3H, CH ),
1.50–1.43 (m, 1H, CH ), 1.26 (s, 3H, CH ), 1.17–1.06 (m,
2H, CH ), 0.89–0.85 (m, 1H, CH ); C NMR (75 MHz,
CDCl
): d ¼ 194:06, 167.61, 161.79, 132.61, 70.36 (C),
52.24 (CH ), 51.29 (CH ), 32.16 (C), 25.26, 17.04 (CH ),
10.98, 9.54 (CH
): d ¼ 3:81
3
2
2
3
2
3
1
3
2
2
2
3
3
3
2
3
4
8
2
); IR (KBr): ~m ¼ 2950 (w), 1715 (s), 1669
ꢀ1
(s), 1606 (w), 1439 (m), 1383 (m), 1248 (m), 1160 (w) cm
;
þ
4
MS (EI, 70 eV): m=z (%): 224.1 (M , 40), 209.0 (30), 177
(48), 164.1 (69), 148.3 (48), 79.2 (30), 43.1 (100), 28.0 (37);
8
8, 1722; (c) Phillips, J. P.; Gillmore, J. G.; Schwartz, P.;
elemental analysis calcd (%) for C12
64.27, H 7.19; found: C 63.74, H 7.71.
16 4
H O (224.25): C
Brammern, L. E., Jr.; Berger, D. J.; Tanko, J. M. J. Am.
Chem. Soc. 1998, 120, 195; (d) for matrix isolation of
tetrafluorospiro[2.5]cycloocta-4,7-dien-6-one: Sander, W.;
Koetting, C.; Huebert, R. J. Phys. Org. Chem. 2000, 13, 561.
. (a) Ward, R. S.; Thatcher, K. S. Tetrahedron Lett. 1981,
14. Synthesis of 5a: TFA (0.04 mL, 0.52 mmol) was added
dropwise at 20 °C to a stirred solution of 4a (0.064 g,
2 2
0.25 mmol) in CH Cl (1.0 mL) and the reaction mixture
5
6
was stirred for 4 h (monitored byTLC). The solvent and
TFA were removed in vacuo and the residue was purified
bycolumn chromatography(silica gel, hexane/eth yl ace-
tate ¼ 1:19) to give 5a (0.084 g, 95%) as a colourless solid;
2
2, 4831; (b) Kende, A. S.; Hebeisen, P.; Sanfilippo, P. J.;
Toder, B. H. J. Am. Chem. Soc. 1982, 104, 4244; (c)
Schultz, A. G.; Taveras, A. G. Tetrahedron Lett. 1996, 37,
5
. (a) Bryson, T. A.; Roth, G. A. Tetrahedron Lett. 1988, 29,
2
1
1
853.
mp 32–33 °C; R
f
¼ 0:58 (ethylacetate–hexane 1:9);
H
NMR (300 MHz, CDCl
(s, 1H, ArH), 5.32 (sep, 1H, J ¼ 6:3 Hz, OCH), 4.37 (t,
2H, J ¼ 8:1 Hz, CH F), 3.08 (t, 2H, J ¼ 8:1 Hz, CH ),
2.53 (s, 3H, CH ), 2.35 (s, 3H, CH ), 1.40 (d, 3H,
J ¼ 6:3 Hz, CH ), 1.39 (d, 3H, J ¼ 6:3 Hz, CH
NMR (75 MHz, CDCl
): d ¼ 170:79 (2C), 160.33, 157.47
(q, J ¼ 42:1 Hz, CF ), 144.09, 139.25, 124.54 (C), 117.33
(CH), 112.53 (C), 69.80 (CH), 66.27, 27.93 (CH ), 21.89
(2C), 20.93, 18.61 (CH
3
): d ¼ 10:77 (s, 1H, OH), 6.71
167; (b) Boger, D. L.; Johnson, D. S. J. Am. Chem. Soc.
990, 112, 5832; (c) Boger, D. L.; Garbaccio, R. M.; Jin,
2
2
Q. J. Org. Chem. 1997, 62, 8875; (d) Boger, D. L.; Boyce,
C. W.; Carpaccio, R. M.; Goldberg, J. A. Chem. Rev.
3
3
1
3
3
3
);
C
1
997, 97, 787; (e) Tietze, L. F.; Hannemann, R.; Buhr, W.;
3
L o€ gers, M.; Menningen, P.; Lieb, M.; Starck, D.; Grote,
T.; D o€ ring, A.; Schuberth, I. Angew. Chem. 1996, 108,
3
2
2
840; Angew. Chem., Int. Ed. Engl. 1996, 35, 2674; (f)
Tietze, L. F.; Buhr, W.; Looft, J.; Grote, T. Chem. Eur. J.
998, 4, 1554.
3
); IR (KBr): ~m ¼ 2959 (s), 1786 (m),
ꢀ
1
1657 (s), 1453 (s), 1375 (s), 1166 (s), 1105 (m) cm ; MS
(EI, 70 eV): m=z (%): 348.6 (M , 68), 306.4 (41), 288.6
(100), 161.2 (93), 91.1 (31), 43.1 (34); the exact molecular
þ
1
7
8
9
. Langer, P.; Bose, G. Angew. Chem. 2003, 115, 4165;
Angew. Chem. Int. Ed. 2003, 42, 4033.
. R o€ mpp Lexikon Naturstoffe; Steglich, W., Fugmann, B.,
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
. Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702.
þ
mass for C16
H
19
O
5
F
confirmed byHRMS (EI, 70 eV).
3
; m=z ¼ 348:1185 ꢁ 2 mD (M ) was
15. Zefirov, N. S.; Kozhushkov, S. I.; Kuznetsova, T. S.
Tetrahedron 1982, 38, 1693.