A regioselective total synthesis of the fungal sesquiterpene (±)-lagopodin A

Article abstract of DOI:10.1055/s-2007-967971

A highly regiocontrolled total synthesis of fungal sesquiterpene lagopodin A, employing a combination of Claisen rearrangement-intramolecular diazoketone cyclopropanation and a highly regioselective cyclopropane ring cleavage, is described. Georg Thieme V

Full text of DOI:10.1055/s-2007-967971

LETTER
655
A Regioselective Total Synthesis of the Fungal Sesquiterpene ( )-Lagopodin A
Total
S
ynthesis of
.the Fungal
S
S
esquiterpene
(
r
)-Lago
i
podin
A
krishna,* R. Ramesh Babu, P. C. Ravikumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Fax +91(80)3600683; E-mail: ask@orgchem.iisc.ernet.in
Received 28 November 2006
OH
OH
O
O
Abstract: A highly regiocontrolled total synthesis of fungal
sesquiterpene lagopodin A, employing a combination of Claisen
rearrangement–intramolecular diazoketone cyclopropanation and a
highly regioselective cyclopropane ring cleavage, is described.
O
O
O
O
HO
OH
HO
HO
OH
Key words: natural products, total synthesis, rearrangement, ring
closure, ring cleavage
1
3
2
O
O
O
O
Helicobasidium mompa Tanaka is a noxious pathogenic
fungus for plants found in Japan and infects subterranean
organs of many plants, causing the ‘violet root rot’. In
1962, Nishikawa reported1 isolation of two colouring mat-
ters, helicobasidin (1, Figure 1) and mompain (2) from the
mycelium cultures of Helicobasidium mompa Tanaka
grown in malt medium during his phytopathological
investigations on this fungus. Almost at the same time,
Takai2 also reported the isolation of orange-yellow pig-
ment from the steam distillate of the culture and identified
as helicobasidin (1). In 1967 Natori et al.3 reported the
isolation and structural elucidation of mompain (2) and a
minor constituent deoxyhelicobasidin (3) from the myce-
lium cultures of Helicobasidium mompa Tanaka. In 1965
Bollinger reported4 the isolation of lagopodin A (4) and
lagopodin B (5) from the cultures of Coprinus lagopus. In
1975 Bottom and Siehr reported5 the isolation of hydroxy-
lagopodin B (6) from single mutant of the basidomycete
Coprinus macrorhizus var. microsporus extracts into the
liquid culture medium. Later, Bulock and Darbyshire
reported6 the isolation of lagopodins A and B (4 and 5),
and the dimeric quinone lagopodin C (7) from Coprinus
lagopus Fr. and Coprinus macrorhizus var. microsporus.
Most of the lagopodins exhibited significant antibiotic
activity.4,6
O
OH
O
5
4
O
O
HO
O
O
O
O
O
HO
O
OH
OH
O
7
6
Figure 1
MeO
MeO
COOEt
OMe
O
OMe
8
9
O
MeO
MeO
+
OMe
OMe
11
10
Lagopodins are interesting synthetic targets because of
the presence of a sterically congested 1-aryl-1,2,2-tri-
methylcyclopentane moiety, in addition to their potential
biological properties. Recently, we have reported the first
total synthesis of lagopodin A7 (4), employing an RCM
reaction of the diene 8 as the key step. However, hydro-
boration–oxidation of the cyclopentene 9 generated a
regiochemical mixture of the cyclopentanones 10 and 11
(Scheme 1). Herein, we report a highly regioselective
total synthesis of ( )-lagopodin A (4).
Scheme 1
The synthetic sequence starting from 2,5-dimethoxy-4-
methylacetophenone8 (12) is depicted in Schemes 2 and 3.
An orthoester Claisen rearrangement9 was employed for
the generation of the first quaternary carbon atom. Thus,
Horner–Wadsworth–Emmons reaction of the aceto-
phenone 12 with triethyl phosphonopropionate and
sodium hydride in refluxing THF generated an E/Z mix-
ture of the cinnamate 13, which on reduction with lithium
aluminum hydride (LAH) in diethyl ether at –50 °C fur-
nished a mixture of the cinnamyl alcohol 14 in an overall
yield of 88%. Although they are separable, since both
the isomers will lead to the same product in Claisen re-
arrangement, the sequence was carried out with a mixture
SYNLETT 2007, No. 4, pp 0655–0657
0
1.
0
3.
2
0
0
7
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-967971; Art ID: D36606ST
© Georg Thieme Verlag Stuttgart · New York

656
A. Srikrishna et al.
LETTER
of alcohols 14. Thermal activation of the cinnamyl alco- atoms.10 It is well established12 that electron-transfer
hol 14 with triethyl orthoacetate and a catalytic amount of reaction of cyclopropyl ketones will proceed in a highly
propionic acid in a sealed tube at 180 °C for 48 hours fur- regioselective manner via cleavage of the cyclopropane
nished the pentenoate 15 in 90% yield.10
bond which has better overlap with the p-orbital of the
ketone group. Accordingly, treatment of bicyclic ketone
18 with lithium in liquid ammonia in the presence of
tertiary butanol generated cyclopentanone 11 in 91%
yield and in a highly regioselective manner.10,13 Finally,
oxidation of compound 11 with ceric ammonium nitrate in
aqueous acetonitrile furnished lagopodin A (4) in 95%
yield, which exhibited spectral data identical to those
reported in the literature.6,7
O
CO2Et
MeO
MeO
a
95%
OMe
OMe
13
12
b
93%
CH2OH
COOEt
MeO
MeO
In conclusion, we have developed a short and convenient
highly regioselective approach for the synthesis of
( )-lagopodin A. A combination of Johnson’s orthoester
Claisen rearrangement, intramolecular diazoketone cyclo-
propanation of a diazoketone and a highly regioselective
cyclopropane ring cleavage was strategically applied for
the generation of the two vicinal quaternary carbon atoms.
Currently, we are investigating the extension of this
approach for the synthesis of helicobasidins and other
lagopodins.
c
90%
OMe
OMe
14
15
Scheme 2 Reagents and conditions: (a) (EtO)2P(O)CH(Me)CO2Et,
NaH, THF, reflux, 8 h; (b) LAH, Et2O, –50 °C, 2 h; (c) MeC(OEt)3,
EtCO2H (catalytic), sealed tube, 180 °C, 48 h.
COOEt
COOH
MeO
MeO
a
92%
Acknowledgment
OMe
15
OMe
17
We thank the Council of Scientific and Industrial Research, New
Delhi for the award of research fellowships to R.R.B. and P.C.R.
80%
b
O
N2
O
References and Notes
MeO
MeO
c
(1) Nishikawa, H. Agric. Biol. Chem. 1962, 26, 696.
(2) Takai, S. Phytopathol. Zeit. 1962, 43, 175.
(3) Natori, S.; Inouye, Y.; Nishikawa, H. Chem. Pharm. Bull.
1967, 15, 380.
(4) Thomson, R. H. Naturally Occurring Quinones; Academic
Press: London, 1971.
48%
OMe
OMe
18
16
91%
d
O
O
(5) Bottom, C. B.; Siehr, D. J. Phytochemistry 1975, 14, 1433.
(6) Bu’Lock, J. D.; Darbyshire, J. Phytochemistry 1976, 15,
2004.
(7) Srikrishna, A.; Lakshmi, B. V.; Ravikumar, P. C.
Tetrahedron Lett. 2006, 47, 1277.
MeO
O
e
95%
OMe
O
11
4
(8) Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans. 1 2000,
3758.
(9) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J.; Li, T. T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem.
Soc. 1970, 92, 741.
Scheme 3 Reagents and conditions: (a) 5% NaOH, MeOH–H2O
(1:1), reflux, 4 h; (b) i. (COCl)2, C6H6, r.t., 3 h; ii. CH2N2, Et2O, 0 °C,
1 h; (c) Cu, CuSO4, c-C6H12, reflux, 6 h, 48%, (1:2.5); (d) i. Li, liq.
NH3, t-BuOH, –33 °C, 15 min; ii. PCC, silica gel, CH2Cl2, r.t., 2 h;
91%; (e) CAN, MeCN–H2O (1:1), r.t., 1 h.
(10) Yields refer to isolated and chromatographically pure
compounds. All the compounds exhibited spectral data (IR,
1H NMR, 13C NMR, and HRMS) consistent with their
structures.
For the creation of the second quaternary carbon atom, an
intramolecular cyclopropanation reaction11 of the diazo-
ketone 16 and regioselective cyclopropane-ring cleavage
was investigated. Thus, hydrolysis of ester 15 with
sodium hydroxide in refluxing aqueous methanol fur-
nished acid 17. Reaction of 17 with oxalyl chloride fol-
lowed by treatment of the resultant acid chloride with an
excess of ethereal diazomethane furnished diazoketone
16. Copper–anhydrous copper sulfate catalysed reaction
of diazoketone 16 resulted in the intramolecular cyclo-
propanation of the resultant carbenoid to furnish a 5:2
diastereomeric mixture of the bicyclo[3.1.0]hexanones 18
containing the requisite two vicinal quaternary carbon
Selected Spectral Data
Ethyl 3-(2,5-Dimethoxy-4-methylphenyl)-3,4-dimethyl-
pent-4-enoate (15): IR (neat): nmax = 1732, 1638, 1505 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.68 (1 H, s), 6.59
(1 H, s), 4.77 (1 H, s), 4.70 (1 H, s), 3.92–3.80 (2 H, m), 3.75
(3 H, s), 3.69 (3 H, s), 3.35 (1 H, d, J = 13.2 Hz), 2.63 (1 H,
d, J = 13.2 Hz), 2.17 (3 H, s), 1.61 (3 H, s), 1.55 (3 H, s), 0.98
(3 H, t, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3 + CCl4): d =
171.8 (C), 151.9 (C), 151.7 (C), 151.2 (C), 131.2 (C), 125.2
(C), 114.9 (CH), 111.2 (CH), 108.6 (CH2), 59.4 (CH2), 55.8
(CH3), 55.7 (CH3), 45.3 (C), 42.8 (CH2), 25.9 (CH3), 20.5
(CH3), 15.9 (CH3), 14.0 (CH3). HRMS: m/z calcd for
C18H26O4Na [M + Na]: 329.1729; found: 329.1733.
Synlett 2007, No. 4, 655–657 © Thieme Stuttgart · New York

LETTER
Total Synthesis of the Fungal Sesquiterpene (±)-Lagopodin A
3-(2,5-Dimethoxy-4-phenyl)-3,4,4-trimethylcyclo-
657
4-(2,5-Dimethoxy-4-methylphenyl)-4,5-dimethyl-
bicyclo[3.1.0]hexan-2-one (18) – minor isomer: IR (neat):
max = 1724, 1674, 1505 cm–1. 1H NMR (300 MHz, CDCl3 +
pentanone (11): IR (neat): nmax = 1740, 1714, 1506 cm–1. 1H
NMR (300 MHz, CDCl3 + CCl4): d = 6.70 (1 H, s), 6.65 (1
H, s), 3.76 (3 H, s), 3.67 (3 H, s), 3.19 (1 H, d, J = 18.3 Hz),
2.34 (1 H, d, J = 18.3 Hz), 2.33 (1 H, d, J = 18.0 Hz), 2.18 (3
H, s), 2.10 (1 H, d, J = 18.0 Hz), 1.50 (3 H, s), 1.18 (3 H, s),
0.82 (3 H, s). 13C NMR (75 MHz, CDCl3 + CCl4): d = 217.1
(C), 151.7 (C), 151.4 (C), 131.1 (C), 125.9 (C), 115.7 (CH),
112.5 (CH), 55.9 (CH3), 55.4 (CH3), 53.2 (CH2), 52.3 (CH2),
48.3 (C), 43.0 (C), 26.1 (2 C, CH3), 25.1 (CH3), 15.9 (CH3).
HRMS: m/z calcd for C17H24O3Na [M + Na]: 299.1623;
found: 299.1615.
n
CCl4): d = 7.05 (1 H, s), 6.65 (1 H, s), 3.81 (3 H, s), 3.74 (3
H, s), 2.60 and 2.07 (2 H, 2 × d, J = 18.3 Hz), 2.19 (3 H, s),
1.71 (1 H, dd, J = 8.4, 2.7 Hz), 1.51 (3 H, s), 1.50 (2 H, s),
1.45–1.20 (2 H, m). 13C NMR (75 MHz, CDCl3 + CCl4): d =
212.5 (C), 152.0 (C), 151.1 (C), 132.0 (C), 125.3 (C), 114.8
(CH), 110.9 (CH), 56.1 (CH3), 55.6 (CH3), 48.5 (CH2), 44.5
(C), 36.1 (C), 35.4 (CH), 25.2 (CH3), 23.8 (CH2), 18.6
(CH3), 16.1 (CH3); major isomer: IR (neat): nmax = 1725,
1666, 1511 cm–1. 1H NMR (300 MHz, CDCl3 + CCl4): d =
6.78 (1 H, s), 6.65 (1 H, s), 3.80 (3 H, s), 3.66 (3 H, s), 2.29
(1 H, d, J = 18.0 Hz), 2.19 (3 H, s), 2.13 (1 H, d, J = 18.0 Hz),
1.81 (1 H, dd, J = 9.0, 3.0 Hz), 1.56 (3 H, s), 1.20–1.00 (2 H,
m), 0.81 (3 H, s). 13C NMR (75 MHz, CDCl3 + CCl4): d =
212.3 (C), 151.6 (C), 151.2 (C), 132.4 (C), 125.7 (C), 114.3
(CH), 110.9 (CH), 56.1 (CH3), 54.8 (CH3), 49.4 (CH2), 44.0
(C), 38.1 (CH), 35.4 (C), 24.1 (CH3), 19.7 (CH2), 17.3
(CH3), 16.0 (CH3). HRMS: m/z calcd for C17H22O3Na [M +
Na]: 297.1467; found: 299.1467.
(11) (a) Stork, G.; Ficini, J. J. Am. Chem. Soc. 1961, 83, 4678.
(b) Burke, S. D.; Grieco, P. A. Org. React. 1979, 26, 361.
(12) (a) Norin, T. Acta Chem. Scand. 1965, 19, 1289.
(b) Dauben, W. G.; Wolf, R. E. J. Org. Chem. 1970, 35,
2361. (c) Srikrishna, A.; Krishnan, K.; Yelamaggad, C. V.
Tetrahedron 1992, 48, 9337.
(13) Varying amount of the corresponding cyclopentanol (by
over-reduction) was also obtained, which was reoxidised to
ketone 11 with PCC and silica gel.
Synlett 2007, No. 4, 655–657 © Thieme Stuttgart · New York