The first total synthesis of a bioactive metabolite, a spirobenzofuran isolated from the fungi Acremonium sp. HKI 0230

Article abstract of DOI:10.1016/j.tetlet.2005.08.049

The first total synthesis of a bioactive metabolite, isolated from the fungi Acremonium sp. HKI 0230, containing a cyclopentaspirobenzofuran carbon framework, employing an Ireland ester Claisen rearrangement and RCM reaction based strategy has been accomp

Full text of DOI:10.1016/j.tetlet.2005.08.049

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7029–7031
The first total synthesis of a bioactive metabolite, a
spirobenzofuran isolated from the fungi Acremonium sp. HKI 0230
A. Srikrishna* and B. Vasantha Lakshmi
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 28 June 2005; revised 5 August 2005; accepted 11 August 2005
Abstract—The first total synthesis of a bioactive metabolite, isolated from the fungi Acremonium sp. HKI 0230, containing a cyclo-
pentaspirobenzofuran carbon framework, employing an Ireland ester Claisen rearrangement and RCM reaction based strategy has
been accomplished.
ꢀ 2005 Elsevier Ltd. All rights reserved.
During the screening for bioactive metabolites from
fungi, Grafe and co-workers discovered that the strain
Acremonium sp. HKI 0230 produces several narrow
spectrum antibacterial compounds. Bioassay guided
fractionation of the mycelium cultures of Acremonium
sp. HKI 0230 led to the isolation of the sesquiterpene
1, containing a novel cyclopentane spirofused benzo-
furan carbon framework incorporating two vicinal
quaternary carbon atoms.1 The spirobenzofuran 1, bio-
synthetically related to the lagopodin family of fungal
metabolites,2 exhibited antimicrobial activity against a
few Gram-positive bacteria such as Bacilus subtilis
ATCC 6623. The presence of an interesting spirocyclic
carbon framework containing two vicinal quaternary
carbon atoms, coupled with the biological activity,
made the spirobenzofuran 1 an attractive synthetic
target. Herein, we describe the first total synthesis of
( )-1.3
atoms could be elaborated into the target molecule 1,
and ring-closing metathesis (RCM)4 of the diene ester
3 was considered ideal for the generation of the spirolac-
tone 2. An Ireland ester Claisen rearrangement5 was
conceived for the generation of the diene ester 3 from
the dimethylallyl ester 4, which could be obtained from
2-arylpentenoic acid 5.
The synthetic sequence starting from 2,5-dimethoxy-4-
methylacetophenone6 6 is depicted in Schemes 2 and
3. To begin with, the acetophenone 6 was converted
into the known7 arylacetate 7. Generation of the lith-
ium enolate of the ester 7 with lithium di-isopropyl-
amide (LDA) and the treatment with allyl bromide
furnished the pentenoate 8 in 89% yield. A dicyclo-
hexylcarbodi-imide (DCC) mediated coupling reaction
was contemplated for the conversion of the ester 8 into
the dimethylallyl ester 4. Thus, hydrolysis of the ester 8
O
HO
O
OH
O
HO
PO
1
MeO
OH
O
COOMe
OMe
The retrosynthetic analysis is depicted in Scheme 1. It
was decided that the spirobenzofuranone 2 containing
a cyclopentene moiety and the two quaternary carbon
O
O
2
1
3
(P=protecting group)
O
O
MeO
COOH
OMe
MeO
Keywords: Fungal metabolites; Spirobenzofuran; RCM reaction;
Ireland ester Claisen rearrangement.
OMe
5
4
*
Corresponding author. Fax: +91 80 23600529; e-mail: ask@
orgchem.iisc.ernet.in
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.049

7030
A. Srikrishna, B. V. Lakshmi / Tetrahedron Letters 46 (2005) 7029–7031
with aqueous sodium hydroxide in methanol furnished
the acid 5. Coupling of the acid 5 with dimethylallyl
alcohol employing DCC and 4-N,N-dimethylamino-
pyridine (DMAP) generated the key intermediate of
the sequence, the esterꢀ 4 in 95% yield. The Ireland
ester Claisen rearrangement of the ester 4 was then
addressed. After exploring a few reaction conditions,
it was found that the generation of the TMS enol ether
of the ester 4 with LDA, trimethylsilyl chloride and tri-
ethylamine in THF at ꢀ70 ꢁC, followed by refluxing
the reaction mixture for 3 h, resulted in the Ireland
ester Claisen rearrangement. Hydrolysis of the reaction
mixture with dilute hydrochloric acid followed by ester-
ification with ethereal diazomethane furnished the ester
3 in 86% yield, whose structure was deduced from its
spectral data. Treatment of the diene-ester 3 with
5 mol % of Grubbsꢁ first generation catalyst [Cl2Ru-
(PCy3)2@CHPh] in methylene chloride for 5 h at room
temperature cleanly furnished the cyclopentene carbox-
ylateꢀ 9 in 97% yield. Treatment of the cyclopentene
carboxylate 9 with boron tribromide in methylene chlo-
ride led to demethylation and concomitant lactonisa-
tion to furnish the spirobenzofuranone 10 in 98%
yield. The phenolic hydroxy group in 10 was protected
as its benzyl ether by treating with potassium carbon-
ate and benzyl bromide in acetone to furnish 11ꢀ in
98% yield. To avoid regiochemical problems at a later
stage, the lactone group was reduced to a lactol and
masked. Thus, controlled reduction of the lactone 11
with di-isobutylaluminium hydride in THF at ꢀ70 ꢁC,
followed by treatment of the resultant lactol 12 with
trimethyl orthoformate and a catalytic amount of
pyridinium p-toluenesulfonate (PPTS) in refluxing
methanol, furnished a 6:1 epimeric mixture of the
ꢀ Yields refer to isolated and chromatographically pure compounds.
All the compounds exhibited spectral data (IR, 1H and 13C NMR
and Mass) consistent with their structures. Selected spectral data for
dimethylallyl ester 4: IR (neat): mmax/cmꢀ1: 1731, 1509. 1H NMR
(300 MHz, CDCl3+CCl4): d 6.72 (1H, s), 6.63 (1H, s), 5.72 (1H, ddt,
J 17.1, 10.2 and 6.9 Hz), 5.26 (1H, m of t, J 7.5 Hz), 5.02 (1H, dd,
J 17.1 and 1.5 Hz), 4.94 (1H, dd, J 10.2 and 1.5 Hz), 4.56 (1H, dd, J
12.0 and 6.9 Hz), 4.49 (1H, dd, J 12.0 and 7.5 Hz), 4.04 (1H, dd, J
8.1 and 6.9 Hz), 3.74 (3H, s), 3.72 (3H, s), 2.71 (1H, dt, J 14.4 and
7.5 Hz), 2.41 (1H, dt, J 14.4 and 6.6 Hz), 2.17 (3H, s), 1.70 (3H, s),
1.65 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): d 173.4 (C), 151.6
(C), 150.3 (C), 137.9 (C), 135.8 (CH), 125.6 (C), 125.1 (C), 119.1
(CH), 116.2 (CH2), 114.1 (CH), 110.3 (CH), 61.1 (CH2), 56.1 (CH3),
55.5 (CH3), 43.6 (CH), 37.0 (CH2), 25.6 (CH3), 17.8 (CH3), 16.1
(CH3). Mass: m/z 318 (M+, 74%), 231 (14), 209 (17), 205 (100), 190
(22), 177 (34), 175 (26), 174 (28), 159 (9), 151 (23), 135 (14). HRMS:
m/z Calcd for C19H26O4Na (M+Na): 341.1729. Found: 341.1713.
For the cyclopentene ester 9: IR (neat): mmax/cmꢀ1 1740, 1504, 1214.
1H NMR (300 MHz, CDCl3+CCl4): d 6.89 (1H, s), 6.62 (1H, s),
5.62 (1H, dt, J 6.0 and 1.8 Hz), 5.56 (1H, dt, J 6.0 and 2.1 Hz), 3.74
(3H, s), 3.68 (3H, s), 3.60 (3H, s), 3.14 and 2.68 (2H, 2·d, J
16.5 Hz), 2.17 (3H, s), 1.19 (3H, s), 1.02 (3H, s). 13C NMR
(75 MHz, CDCl3+CCl4): d 175.0 (C), 150.7 (C), 150.6 (C), 141.8
(CH), 129.1 (C), 125.6 (C), 125.0 (CH), 114.6 (CH), 112.3 (CH),
61.1 (C), 56.0 (CH3), 55.9 (CH3), 51.2 (CH3), 50.2 (C), 42.7 (CH2),
26.0 (CH3), 23.9 (CH3), 16.1 (CH3). Mass: m/z 304 (M+, 69%), 272
(100), 257 (34), 245 (77), 229 (31), 175 (27), 165 (24), 152 (43), 115
(42). HRMS: m/z Calcd for C18H24O4Na (M+Na): 327.1572. Found
327.1568. For the spiro lactone 11: IR (neat): mmax/cmꢀ1 1799. 1H
NMR (300 MHz, CDCl3+CCl4): d 7.40–7.25 (5H, m), 6.88 (1H, s),
6.74 (1H, s), 5.78 (1H, dt, J 5.7 and 2.1 Hz), 5.60 (1H, dt, J 5.7 and
2.1 Hz), 5.03 and 4.98 (2H, 2·d, J 12.0 Hz), 3.02 (1H, dt, J 16.5 and
2.1 Hz), 2.64 (1H, dt, J 16.5 and 2.1 Hz), 2.29 (3H, s), 1.14 (3H, s),
0.83 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): d 178.6 (C), 153.1
(C), 146.8 (C), 140.3 (CH), 137.2 (C), 128.6 (2C, CH), 128.1 (C),
127.9 (CH), 127.3 (2C, CH), 126.3 (CH), 112.7 (CH), 108.7 (CH),
70.9 (CH2), 59.2 (C), 52.3 (C), 43.0 (CH2), 25.1 (CH3), 24.5 (CH3),
16.9 (CH3). Mass: m/z 334 (M+, 25%), 243 (20), 215 (22), 91 (100).
HRMS: m/z Calcd for C22H22O3Na (M+Na): 357.1467. Found:
357.1474. For the spiro ketone 16: IR (neat): mmax/cmꢀ1 1743. 1H
NMR (300 MHz, CDCl3+CCl4): d 7.40–7.20 (5H, m), 6.65 (1H, s),
6.43 (1H, s), 5.34 (1H, s), 4.99 and 4.95 (2H, 2·d, J 12.0 Hz), 3.47
(3H, s), 2.96 and 2.42 (2H, 2·d, J 19.2 Hz), 2.27 and 2.15 (2H, 2·d,
J 18.3 Hz), 2.25 (3H, s), 1.08 (3H, s), 0.79 (3H, s). 13C NMR
(75 MHz, CDCl3+CCl4): d 215.6 (C), 151.6 (C), 151.4 (C), 137.5
(C), 128.6 (2C, CH), 128.3 (C), 127.8 (CH), 127.3 (2C, CH), 126.8
(C), 112.6 (CH), 109.1 (CH), 109.0 (CH), 71.1 (CH2), 59.9 (C), 56.0
(CH3), 52.7 (CH2), 42.8 (CH2), 41.7 (C), 24.5 (CH3), 24.2 (CH3),
16.9 (CH3). HRMS: m/z Calcd for C23H26O4Na (M+Na): 389.1729.
Found: 389.1739. For the spirobenzofuran 1: IR (neat): mmax/cmꢀ1
methyl acetals 13.
T
heanti-stereochemistry was
assigned to the methoxy group in the major isomer
13a on the basis of kinetic and thermodynamic consi-
derations. A hydroboration–oxidation strategy was
explored for the introduction of the ketone group into
the cyclopentane ring. Consequently, reaction of the
spiroacetal 13a with freshly prepared diborane in
THF followed by oxidation of the alkyl borane with
30% hydrogen peroxide and 3 N aqueous sodium
hydroxide furnished a 3:1 regioisomeric mixture of
the cyclopentanols 14 and 15, in 96% yield, in a highly
stereoselective manner, which were separated by col-
umn chromatography on silica gel. Oxidation of the
alcohols 14 and 15 with pyridinium chlorochromate
(PCC) and silica gel in methylene chloride furnished
the ketones 16ꢀ and 17 in excellent yields, whose struc-
tures were deduced from their spectral data. Hydrolysis
of the acetal group in the spiroketone 16 with 2:1 acetic
acid–water and a catalytic amount of trifluoroacetic
acid at reflux furnished the lactol 18 in 86% yield.
Finally, hydrogenolysis of the benzyl group with 10%
palladium on charcoal as the catalyst at one atmo-
spheric pressure of hydrogen (balloon) in ethanol fur-
nished quantitatively the spirobenzofuranꢀ ( )-1. T he
synthetic spirobenzofuran 1 exhibited 1H and 13C
NMR spectral data (in DMSO-d6) identical to those
reported for the natural product.
In summary, we have accomplished the first total syn-
thesis of the spirobenzofuran 1 isolated from the myce-
lial cultures of the fungi Acremonium sp. HKI 0230 in an
efficient manner, confirming the structure of the natural
product. A combination of an Ireland ester Claisen rear-
rangement and RCM reactions was employed for the
creation of two vicinal quaternary carbon atoms. Com-
pound 1 was obtained in 13 steps from the known aryl-
acetate 7 in >30% overall yield.
1
3407, 1735, 1172, 1120. H NMR (300 MHz, CDCl3): d 6.65 (1H, s),
6.47 (1H, s), 5.86 (1H, s), 3.06 and 2.51 (2H, 2·d, J 18.9 Hz), 2.45
and 2.26 (2H, 2·d, J 18.3 Hz), 2.22 (3H, s), 1.12 (3H, s), 0.90 (3H,
s). 13C NMR (75 MHz, CDCl3): d 217.0 (C), 151.0 (C), 148.5 (C),
127.0 (C), 124.8 (C), 112.3 (CH), 111.2 (CH), 102.6 (CH), 60.1 (C),
52.7 (CH2), 42.9 (CH2), 41.8 (C), 24.3 (CH3), 24.1 (CH3), 16.2
(CH3). HRMS: m/z Calcd for C15H18O4Na (M+Na): 285.1103.
Found: 285.1105.

A. Srikrishna, B. V. Lakshmi / Tetrahedron Letters 46 (2005) 7029–7031
7031
O
COOMe
MeO
MeO
MeO
COOMe
OMe
a
b
OMe
OMe
69%
89%
7
6
8
c
96%
O
O
COOH
MeO
MeO
MeO
MeO
e
d
COOMe
OMe
86%
95%
OMe
OMe
4
5
3
97%
f
HO
PhH2CO
g
98%
h
98%
COOMe
OMe
O
O
O
O
9
10
11
Scheme 2. Reagents and conditions: (a) I2 (2 equiv), HC(OMe)3, rt, 6 h; reflux, 6 h; (b) LDA, THF; CH2@CHCH2Br, ꢀ70 ꢁC!rt, 7 h; (c) 10%
NaOH, MeOH–H2O (1:1), reflux, 7 h; (d) DCC, DMAP (catalytic), Me2C@CHCH2OH, CH2Cl2, rt, 5 h; (e) (i) LDA, THF; TMSCl, NEt3, ꢀ70 ꢁC,
30 min; rt, 6 h; reflux, 3 h; (ii) dil. HCl, 40 min; (iii) CH2N2, Et2O, 0 ꢁC, 30 min; (f) Cl2Ru(PCy3)2@CHPh (5 mol %), CH2Cl2, rt, 5 h; (g) BBr3,
CH2Cl2, ꢀ70 ꢁC, 1.5 h; (h) K2CO3, PhCH2Br, acetone, rt, 6 h.
PhH2CO
PhH2CO
PhH2CO
a
OMe
OMe
b
O
OH
O
100%
O
O
89%
13b
12
( 1 : 6 )
11
+
HO
OH
PhH2CO
c
PhH2CO
PhH2CO
O
96%
OMe
OMe
+
O
O
13a
( 3 : 1 )
14
15
d
d
95%
95%
O
O
PhH2CO
PhH2CO
OMe
OMe
O
O
16
17
O
O
O
PhH2CO
PhH2CO
HO
e
f
100%
OMe
OH
OH
86%
O
O
O
( )-1
16
18
Scheme 3. Reagents and conditions: (a) DIBAL-H, THF, ꢀ70 ꢁC, 1.5 h; (b) MeOH, HC(OMe)3, PPTS, reflux, 40 min; (c) (i) NaBH4, BF3ÆEt2O,
THF, 0 ꢁC!rt, 1 h; (ii) 30% aq H2O2, 3 N aq NaOH, 0 ꢁC!rt, 7 h; (d) PCC, silica gel, CH2Cl2, rt, 1 h; (e) AcOH–H2O (2:1), CF3COOH (catalytic),
reflux, 14 h; (f) 10% Pd/C, H2, EtOH, 1 atm, 1.5 h.
3. To the best of our knowledge there is no report on the
synthesis of spirobenzofuran 1.
Acknowledgements
4. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
We thank the Council of Scientific and Industrial Re-
search, New Delhi for the award of a research fellowship
to B.V.L.
4450; (b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39,
¨
3013–3043; (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18–29.
5. Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94,
5897; Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org.
Chem. 1991, 56, 650; Gilbert, J. C.; Yin, J.; Fakhreddine, F.
H.; Karpinski, M. L. Tetrahedron 2004, 60, 51.
6. Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans. 1 2000,
3758–3764.
References and notes
1. Kleinwachter, P.; Schlegel, B.; Dorfelt, H.; Grafe, U.
J. Antibiot. 2001, 54, 526–527.
2. BuꢁLock, J. D.; Darbyshire, J. Phytochemistry 1976, 15,
2004; Bottom, C. B.; Siehr, D. J. Phytochemistry 1975, 14,
1433–1436.
7. Maruyama, K.; Kozuka, T. Bull. Chem. Soc. Jpn. 1978, 51,
3586–3589.