Synthesis of spirocyclic butenolides by ring closing metathesis

Article abstract of DOI:10.1055/s-2002-34906

Spirocyclic butenolides were efficiently prepared by a ring closing metathesis strategy.

Full text of DOI:10.1055/s-2002-34906

LETTER
1841
Synthesis of Spirocyclic Butenolides by Ring Closing Metathesis
Synthesis of
S
e
pirocyclic
B
t
utenol
e
ides r Langer,* Uwe Albrecht
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
Fax +40(3834)864373; E-mail: planger@gwdg.de
Received 29 August 2002
O
Abstract: Spirocyclic butenolides were efficiently prepared by a
ring closing metathesis strategy.
HO
H2C=CHMgBr
R
R
(CH2)n
(CH2)n
Key words: butenolides, catalysis, metathesis, ruthenium, spiro-
compounds
_
THF, 78 °C
2a-g
1a-g
H2C=CH(CO)Cl
NEt3, THF, 0 °C
Spirocyclic butenolides are of biological relevance and
are present in a variety of pharmacologically relevant
natural products, such as chlorotricolide1a,b and hydnufer-
ruginine.1c Although a number of methods for the prepa-
ration of spirocyclic butenolides have been reported, more
efficient syntheses need to be developed. The ring closing
metathesis (RCM) reaction has been applied to the synthe-
sis of oxygen and nitrogen heterocycles.2 In the oxygen
series most work has been focussed on the synthesis of
dihydropyrans.3 In contrast, the synthesis of butenolides
has not been greatly explored so far.4 Herein, we wish to
report the synthesis of spirocyclic butenolides by RCM.5
This method is of preparative usefulness, due to its sim-
plicity and efficiency (Figure 1).
O
O
5 (5 mol-%)
O
O
Ti(OiPr)4
R
R
(CH2)n
(CH2)n
CH2Cl2, 35 °C
PCy3
Ru
Ph
4a-g
3a-g
Cl
Cl
5 =
PCy3
Scheme 1 Synthesis of butenolides 4a–g by RCM
Table 1 Products and Yields from RCM
O
OPG
O
O
2,3,4
n
2
1
3
4
6
8
2
2
R
% (2)a
83
% (3)a
43
% (4)a
57
H
HO
OGP
O
O
a
b
c
d
e
f
H
OH
H
H
O
O
MeO
H
58
48
66
76
78
63
70
80
80
O
O
OH
H
66
58
O
Spirotetronic Acid Fragment
of Chlorotricolide
Hydnuferruginin
H
74
45
Figure 1
H
59
42
H
80
71
The reaction of cyclohexanone (1a) with vinyl magne-
sium bromide afforded the known alcohol 2a which was
transformed into the ester 3a by treatment with acrylic
chloride (Scheme 1, Table 1).6 Ring closing metathesis
using Grubbs’ catalyst (5) afforded the desired spirocyclic
butenolide 4a, however, in only low yield. Optimal yields
were eventually obtained when the reaction was carried
out at 35 °C in CH2Cl2 in the presence of catalytic
amounts of Ti(iPrO)4.7 Following the work of Fürstner et
al. the Lewis acid was used to avoid interuption of the cat-
alytic cycle by chelation of the substrate carbonyl to the
metal.8
g
g
Me
Me
49
30
–
80b
a Isolated yields: for 2g, 3g and 4g: syn/anti > 98:2.
b Prepared directly from 1g at 0 °C without isolation of 2g.
To study the preparative scope of the methodology, the
ring size and the substituents of the cycloalkanone were
systematically varied (Scheme 1, Table 1). Starting with
cyclohexanone, cyclopentanone, cycloheptanone, cyclo-
octanone, cyclodecanone and cyclododecanone, the esters
3a–f were prepared in two steps. The RCM of 3a–f
proceeded uneventfully and afforded the spirocyclic
butenolides 4a–f in good yields. The synthesis of butenol-
ides containing two stereogenic centers was next studied.
The reaction of vinylmagnesiumbromide with 2-methyl-
Synlett 2002, No. 11, Print: 29 10 2002.
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© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1842
P. Langer, U. Albrecht
LETTER
cyclohexanone proceeded with very good diastereoselec-
tivity to give the known alcohol 2g.9 This compound was
successfully transformed into the diastereomerically pure
butenolide 4g via the ester 3g. The overall yield of 3g
could be significantly improved by direct synthesis from
1g (without isolation of 2g). The use of -tetralone (6) as
the starting material was next studied. Grignard reaction
of 6 gave the alcohol 7, which was transformed into the
ester 8. Ring closing metathesis of 8 afforded the known
butenolide 9 (Scheme 2).10
References
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3041. (b) Ireland, R. E.; Varney, M. D. J. Org. Chem. 1986,
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(2) Reviews: (a) Schuster, M.; Blechert, S. Angew. Chem., Int.
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(b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
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(5) For related work, see: (a) Bassindale, M. J.; Hamley, P.;
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(b) Michaut, M.; Santelli, M.; Parrain, J.-L. J. Organomet.
Chem. 2000, 606, 93.
O
HO
H2C=CHMgBr
_
THF, 78 °C
(6) (a) Herz, W.; Juo, R.-R. J. Org. Chem. 1985, 50, 618.
(b) Wang, C.; Russell, G. A. J. Org. Chem. 1999, 64, 2066.
(7) Representative Experimental Procedure: To a CH2Cl2-
solution (30 mL) of 3f (264 mg, 1 mmol) was added
Ti(iPrO)4 (42 mg, 0.15 mmol) and the solution was stirred
for 1 h at 35 °C. A CH2Cl2-solution (10 mL) of 5 (82 mg, 0.1
mmol) was subsequently added and the reaction mixture was
stirred at 35 °C for 48 h. The solvent was removed in vacuo
and the residue was purified by column chromatography
(silica gel, petroleum ether/ether = 3:1) to give 4f as a white
solid (165 mg, 0.70 mmol, 70%). Spectroscopic data of 4f:
1H NMR (CDCl3, 250 MHz): = 1.23–1.40 (m, 13 H, CH2),
1.41–1.60 (m, 7 H, CH2), 1.70–1.82 (m, 2 H, CH2), 5.95 (d,
J = 6 Hz, 1 H, CH), 7.48 (d, J = 6 Hz, 1 H, CH). 13C NMR
(CDCl3, 50 MHz): = 19.94, 21.79, 22.32, 25.68, 25.96
31.86, 91.87, 119.81, 160.79, 172.43. IR (KBr): = 3088
(w), 2957 (s), 2937 (s), 2864 (m), 2847 (m), 1743 (s), 1472
(s), 1444 (m)cm–1. MS (70 eV): m/z (%) = 236 (100) [M+],
208 (16), 179 (12), 165 (28), 151 (28); the exact molecular
mass for C15H24O2 m/z = 236.1776 2 mD [M+] was
confirmed by HRMS (EI, 70 eV). Anal. Calcd for C15H24O2:
C, 76.23; H, 10.24. Found: C, 76.10; H, 10.76. All new
compounds gave satisfactory spectroscopic data and correct
elemental analyses and/or high resolution mass data.
(8) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130.
76%
6
7
H2C=CH(CO)Cl
NEt3, THF, 0 °C
20%
O
O
5 (5 mol-%)
O
O
Ti(OiPr)4
CH2Cl2, 35 °C
61% (b.o.r.s.m.)
8
9
Scheme 2 Synthesis of butenolide 9 (b.o.r.s.m. = based on recover-
ed starting material)
In summary, we have developed a novel synthesis of phar-
macologically relevant spirocyclic butenolides using
RCM. Our strategy is currently applied to the synthesis of
enantiomerically pure butenolides and natural products.
(9) Molander, G. A.; Burkhardt, E. R.; Weinig, P. J. Org. Chem.
1990, 55, 4990.
(10) Carda, M.; Castillo, E.; Rodríguez, S.; Uriel, S.; Marco, J. A.
Synlett 1999, 10, 1639.
Acknowledgement
P. L. thanks Professor A. de Meijere for his support. Financial sup-
port from the Fonds der Chemischen Industrie e. V. (Liebig-schol-
arship for P. L.) and from the Deutsche Forschungsgemeinschaft
(Heisenberg-scholarship for P. L. and Normalverfahren) is grate-
fully acknowledged.
Synlett 2002, No. 11, 1841–1842 ISSN 0936-5214 © Thieme Stuttgart · New York