Synthesis and reactions of hydroxyspiro[5.2]cyclooctenones based on the cyclization of the dianions of acetone and diethyl 2-oxopropylphosphonate with 1,1-diacylcyclopropanes

Article abstract of DOI:10.1016/j.tetlet.2008.02.036

The cyclization of the dianions of diethyl 2-oxopropylphosphonate and of acetone with 1,1-diacylopropanes afforded hydroxyspiro[5.2]cyclooctenones which were transformed, by homo-Michael reactions with tetrabutylammonium halides, into various functionaliz

Full text of DOI:10.1016/j.tetlet.2008.02.036

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2254–2257
Synthesis and reactions of hydroxyspiro[5.2]cyclooctenones based
on the cyclization of the dianions of acetone and diethyl
2-oxopropylphosphonate with 1,1-diacylcyclopropanes
Nasir Rasool a, Muhammad A. Rashid a, Muhammad Adeel a, Helmar Gorls c,
¨
Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V.an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
c Institut fu¨r Anorganische und Analytische Chemie, Universita¨t Jena, Lessingstraße 8, D-07743 Jena, Germany
Received 5 December 2007; revised 4 February 2008; accepted 6 February 2008
Available online 12 February 2008
Abstract
The cyclization of the dianions of diethyl 2-oxopropylphosphonate and of acetone with 1,1-diacylopropanes afforded hydroxy-
spiro[5.2]cyclooctenones which were transformed, by homo-Michael reactions with tetrabutylammonium halides, into various function-
alized phenols or their dimers.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyclizations; Cyclopropanes; Dianions; Regioselectivity; Spiro-compounds
Spirocyclopropanes are present in a number of pharma-
cologically interesting natural products, such as the cyto-
toxic illudins (Fig. 1),1 CC-1065, or duocarmycin SA.2
The illudins belong to the group of alkylating anticancer
agents. The reaction of a nucleophile (such as glutathione)
with the unsaturated ketone moiety results in the formation
of a cyclohexadiene which rapidly undergoes an aromati-
zation with concurrent ring opening of the cyclopropane
moiety and alkylation of the DNA.1 We have reported
the TiCl4-mediated domino ‘[3+3]-cyclization-homo-
Michael’ reaction of 1,3-bis(silyl enol ethers) with 1,1-di-
acylcyclopropanes.3 These reactions proceed by in situ
formation of spiro[2.5]cycloocta-4,7-dien-6-ones which are
subsequently cleaved by the action of TiCl4. In their pio-
neering work, Baird and Winstein studied the synthesis of
spiro[2.5]cycloocta-4,7-dien-6-ones and their reaction with
various nucleophiles.4 Padwa and co-workers reported
interesting cyclization reactions of diazo-compounds which
allow a convenient synthesis of illudins.5 Recently, we have
reported6 the synthesis of ester-substituted 1-hydroxyspi-
ro[5.2]cyclooct-4-en-3-ones, precursors of spiro[2.5]cyclo-
octa-4,7-dien-6-ones, based on cyclization reactions of
1,3-dicarbonyl dianions. The homo-Michael reaction of
these highly activated7,8 spirocyclopropanes, which
exhibit a considerable anti-proliferative activity against
human leukemia HL60 cells, with various nucleophiles
results in the formation of functionalized phenols. This
Me
Me
O
OH
X
Me
Me
Me
HO
Me
R
Me
O
OH
Pterosins
Illudin M
X = OH, OMe, Cl
R = H, Me
Fig. 1.
*
Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.036

N. Rasool et al. / Tetrahedron Letters 49 (2008) 2254–2257
2255
transformation is related to the biosynthesis of the carcin-
OH
O
ogenic pterosins (Fig. 1), which were isolated from the
bracken fern Pteridium aquilinium.9 It was shown earlier
that the pterosins are formed from their direct biogenetic
precursor, the spirocyclopropane ptaquilosin, by treatment
with acid. It was proposed that the pterosins, ptaquilosin
and illudin M are all formed from farnesyl phosphate via
a common biosynthetic intermediate.1,9 Herein, we report
what are, to the best of our knowledge, the first cyclizations
of the dianions of diethyl 2-oxopropylphosphonate and of
acetone with 1,1-diacylcyclopropanes. These reactions pro-
vide a convenient access to hydroxyspiro[5.2]cyclooctenon-
es. Homo-Michael reactions of these products with
tetrabutylammonium halides allow for a convenient syn-
thesis of functionalized phenols which are not readily avail-
able by other methods.
N(
n
Bu)4X
i
HO
Me
Me
R
X
R
4a-f
3a,b
.
H2O
BF3 OEt2
_
+
N(n
Bu)4
O
O
+
N(nBu)4
.
BF3 OEt2
Me
R
X
Me
R
X_
C
D
The cyclization6 of the dianion10,11 of diethyl 2-
oxopropylphosphonate (1), generated by means of LDA,
with 1,1-diacetylcyclopropane (2a) and 1-acetyl-1-benzoyl-
cyclopropane (2b) afforded the 1-hydroxyspiro[5.2]cyclo-
oct-4-en-3-ones 3a and 3b, respectively (Scheme 1). The
formation of 3a,b can be explained by cyclization (interme-
diate A), elimination of lithium diethylphosphate (interme-
diate B) and subsequent protonation upon the addition of
water. The reaction can be regarded as a domino ‘aldol/
Horner–Wadsworth–Emmons (HWE)’ reaction.
The BF3ꢀOEt2-mediated reaction of 3a,b with tetrabutyl-
ammonium halides afforded the phenols 4a–f containing a
halogenated side chain (Scheme 2, Table 1). Products 4a–f
were presumably formed by BF3ꢀOEt2-mediated elimina-
tion of water to give a highly reactive spiro[2.5]cycloocta-
4,7-dien-6-one (intermediate C). The cyclopropane moiety
is subsequently cleaved by BF3ꢀOEt2-mediated attack of
Scheme 2. Reaction of 3a,b with nBu4NX. Reagents and conditions: (i)
nBu4NX (1.0 equiv), BF3ꢀOEt2(0.5 equiv), ꢁ78?20 °C, 12 h.
Table 1
Synthesis of phenols 4a–f
4
R
X
Yielda (%)
a
b
c
d
e
f
Me
Me
Me
Ph
Ph
Ph
Cl
Br
I
Cl
Br
I
73
68
63
70
75
81
a
Isolated products.
the halide ion to give a phenolate (intermediate D), which is
protonated upon the addition of water (aqueous work-
up).6
The cyclization of 1,1-diacylcyclopropanes 2a–d with the
dianion11,12 of acetone (5), generated by the addition of 5
to a THF-suspension of potassium hydride and subsequent
addition of TMEDA and nBuLi, afforded the 1-hydroxy-
spiro[5.2]cyclooct-3-en-5-ones 6a–d (Scheme 3, Table 2).
The unexpected formation 6a–d, which are regioisomers
of products 3a,b, can be explained as follows: the reaction
of dianion E with 2a–d resulted in internal protonation.
The attack of the monoanion of acetone onto the enolate
of 2a–d afforded intermediate F. The latter underwent a
cyclization to give G which afforded 6a–d upon aqueous
work-up. Products 6b–d were formed by regioselective
attack of dianion E onto the aroyl rather than the acetyl
group of 2b–d. This result can be explained based on the
mechanism suggested. Alternatively, a direct attack of
dianion E onto 2a–d can be discussed. However, this
mechanism is less likely as the first attack of E should occur
onto the more reactive acetyl rather than the benzoyl
group.
O
O
P(OEt)2
O
1
i
O
O
R
HO
Me
+
R
Me
3a (R = Me): 31%
3b (R = Ph): 30%
2a,b
H2O
O
O
O
P(OEt)2
LiO
Me
OLi
LiO
Me
R
R
_
LiOPO(OEt)2
B
A
The BF3ꢀOEt2-mediated reaction of 6a with tetrabutyl-
ammonium halides afforded the phenols 7a–c (Scheme 4,
Table 3).13 Their formation can be explained by a
Scheme 1. Synthesis of spirocyclopropanes 3a,b. Reagents and conditions:
(i) (1) LDA (2.0 equiv), 1 (1.0 equiv), THF, 1 h, 0 °C; (2) 2a,b (1.0 equiv),
ꢁ78?20 °C, 14 h.

2256
N. Rasool et al. / Tetrahedron Letters 49 (2008) 2254–2257
Table 3
O
O
Synthesis of phenols 7 and their dimers 8
Me
Yield (%) (7)a Yield (%) (8)a
Me
R
7
8
R
X
O
a
b
c
d
e
f
a
a
a
b
b
b
c
Me
Me
Me
Ph
Ph
Ph
Cl
Br 77
I
Cl
Br
I
65
0
0
0
66
63
79
51
59
50
0
2a-d
OH
O
R
i
81
0
0
5
6a-d
H2O
O Me
0
g
h
i
4-ClC6H4 Br 30
c
4-ClC6H4
4-FC6H4
4-FC6H4
I
Cl
I
33
0
41
d
d
_
K+
j
_
a
2
Li+
Isolated products.
O
_
K+, Li+
O
O
R
E
G
2a-d
O_
Li+
O
Me
O
Me
K+
_
+
K+ O_
_
Li+
O
O
R
R
F
Scheme 3. Synthesis of 6a–d. Reagents and conditions: (i) (1) KH, THF,
0 °C; (2) nBuLi, TMEDA, ꢁ20 °C; (3) 2a–d ꢁ30?15 °C, 15 h.
Table 2
Synthesis of spirocyclopropanes 6a–d
Yielda (%)
Fig. 2. Ortep plot of 7a.
6
R
a
b
c
Me
Ph
4-ClC6H4
4-FC6H4
41
33
31
30
mediated reaction of 6b with tetrabutylammonium chloride
resulted in the formation of the halogen-free 10-membered
cyclic diether 8b in 66% yield. The employment of tetra-
butylammonium bromide and iodide afforded 8b in 63%
and 79% yield, respectively. The formation of 8b can be
explained by direct opening of the cyclopropane moiety
of one molecule of 6b with the oxygen of another molecule,
followed by cyclization. The reaction of spirocyclopropane
6c with tetrabutylammonium bromide afforded a separable
mixture of phenol 7g (30%) and dimer 8c (51%). The
employment of tetrabutylammonium iodide resulted in
the formation of phenol 7h and dimer 8c in 33% and
59% yield, respectively. The reaction of spirocyclopropane
6d with tetrabutylammonium chloride gave exclusively
dimer 8d (50%), whereas phenol 7j (41%) was isolated when
tetrabutylammonium iodide was used. This result can be
explained by the higher nucleophilicity of iodide compared
to chloride. The attack of the iodide ion onto the cyclo-
propane moiety is more rapid than the attack of the oxygen
atom of another molecule. In conclusion, the product
distribution seems to depend on the substituent R and on
the tetraammonium halide employed.
d
a
Isolated products.
Me
O
R
Me
OH
Me
NBu4X
+
O
R
HO
R
X
i
O
R
6a-d
Me
7a-j
8a-d
Scheme 4. Reaction of 6a–d with nBu4NX. Reagents and conditions: (i)
nBu4NX (1.0 equiv), BF3ꢀOEt2 (0.5 equiv), ꢁ78?20 °C, 12 h.
mechanism related to the one discussed for 4a–f (vide
supra). The structure of 7a was independently confirmed by
X-ray crystal structure analysis (Fig. 2).14 The BF3ꢀOEt2-

N. Rasool et al. / Tetrahedron Letters 49 (2008) 2254–2257
2257
7. (a) Houben-Weyl, Methoden der Organischen Chemie, In Carbocyclic
Three-Membered Ring Compounds, 4th ed.; de Meijere, A., Ed.;
Thieme: Stuttgart, 1996; Vol. E17; (b) Houben-Weyl, The Chemistry
of the Cyclopropyl Group, Rappoport, Z., Ed.; Wiley: Chichester,
1987.
8. Reactions of acceptor-substituted cyclopropanes have been classified
by Danishefsky in terms of ‘strictly nucleophilic ring openings’,
‘electrophilically assisted ring openings’ and ‘spiro-activations’:
Danishefsky, S. J. Acc. Chem. Res. 1979, 66. In the domino
‘[3+3]-cyclization-homo-Michael’ reaction reported herein two
In conclusion, the cyclization of 1,1-diacylopropanes
with the dianions of diethyl 2-oxopropylphosphonate and
acetone afforded hydroxyspiro[5.2]cyclooctenones which
were transformed, by homo-Michael reactions, into func-
tionalized phenols or their dimers. The preparative scope
and applications of the methodology reported is currently
being studied.
Acknowledgement
effects are operating: (a)
a ‘dynamic spiro-activation’ and (b)
activation by an electrophile. For a dynamic spiro activation, see:
Zefirov, N. S.; Kozhushkov, S. I.; Kuznetsova, T. S. Tetrahedron
1982, 38, 1693.
Financial support by the State of Pakistan (scholarships
for M.A.R. and N.R.) is gratefully acknowledged.
9. (a) McMorris, T. C.; Voeller, B. Phytochemistry 1971, 10, 3253; (b)
Yoshishira, K.; Fukuoka, M.; Kuroyanagi, M.; Natori, S. Chem.
Pharm. Bull. 1971, 19, 1491; (c) Bardouille, V.; Mootoo, B. S.;
Hirotsu, K.; Clardy, J. Phytochemistry 1978, 17, 275; (d) Sengupta, P.;
Sen, M.; Niyogi, S. K.; Pakrashi, S. C.; Ali, E. Phytochemistry 1976,
15, 995; (e) Yoshihira, K.; Fukuoka, M.; Kuroyanagi, M.; Natori, S.;
Umeda, M.; Morohoshi, T.; Enomoto, M.; Saito, M. Chem. Pharm.
Bull. 1978, 26, 2346.
References and notes
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13. Typical procedure for the synthesis of functionalized phenols from
spirocyclopropanes: To a CH2Cl2 solution (15 mL) of 8-hydroxy-6,8-
dimethylspiro[2.5]oct-5-en-4-one (6a) (334 mg, 2.0 mmol) and of
nBu4NCl (554 mg, 2.0 mmol) was dropwise added BF3ꢀOEt2
(0.24 mL, 2.0 mmol) at ꢁ78 °C under argon atmosphere. The solution
was allowed to warm to 20 °C over 6 h and was stirred for additional
6 h at 20 °C. The solution was filtered and the filtrate was poured into
hydrochloric acid (1.0 M). The organic and the aqueous layer were
separated and the latter was extracted with CH2Cl2. The combined
organic layers were washed with brine, dried (Na2SO4), filtered, and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, hexane–EtOAc) to give 7a as a colourless
solid (242 mg, 65%). 2-(2-Chloroethyl)-3,5-dimethylphenol (7a): 1H
NMR (250 MHz, CDCl3): d 2.24 (s, 3H, CH3), 2.30 (s, 3H, CH3), 3.11
(t, 2H, J = 8.0 Hz, CH2), 3.67 (t, 2H, J = 7.4 Hz, CH2), 6.44 (s, 1H,
ArH), 6.61 (s, 1H, ArH). 13C NMR (62 MHz, CDCl3): d 19.4 (CH3),
19.5 (CH3), 30.2 (CH2), 43.2 (CH2), 113.8 (CH), 120.0 (C), 123.8
(CH), 137.5, 138.2, 153.8 (C). IR (KBr): ~m ¼ 3350 (m), 3453 (S), 2870
(m), 1716 (s), 1632 (s), 1562 (m), 1439 (s), 1325 (m), 1142 (m), 1152 (s),
1122 (w), 834 (m), cmꢁ1. GC–MS (EI, 70 eV): m/z (%): 186 (M+, 37Cl,
9), 184 (M+, 35Cl, 21), 148 (6), 135 (100), 105 (11), 91 (13), 77 (14).
HRMS (EI): calcd for C10H13OCl [M+, 35Cl]: 184.06494, found:
184.06527.
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14. CCDC-676879 contains all crystallographic details of this publication
and are available free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or can be ordered from the following address:
Cambridge Crystallographic Data Centre, 12 Union Road, GB-
Cambridge CB21EZ; Fax: (+44)1223-336-033; or deposit@ccdc.
cam.ac.uk.