First total synthesis of (±)-hyperolactone A

Article abstract of DOI:10.1039/a704159d

The first total synthesis of (±)-hyperolactone A, isolated from Hypericum chinense L., is accomplished from 3-furoic acid and 2-methylbutanal.

Full text of DOI:10.1039/a704159d

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First total synthesis of (±)-hyperolactone A
Daisuke Ichinari,a Toshihiko Ueki,a Kazuo Yoshiharab and Takamasa Kinoshita*a
a Department of Chemistry, Faculty of Science, Osaka City University, Sugimoto-cho, Sumiyoshi-ku, Osaka 558, Japan
b Suntory Institute for Bioorganic Research, Shimamoto-cho, Osaka 618, Japan
2 + 4
The first total synthesis of ( )-hyperolactone A, isolated
from Hypericum chinense L., is accomplished from 3-furoic
i
OH
O
acid and 2-methylbutanal.
O
O
O
O
Hyperolactone A1 is a unique spiro compound isolated from
Hypericum chinense L., which has a 2-alkyl-9-methyl-9-vinyl-
1,7-dioxaspiro[4,4]non-2-ene-4,6-dione skeleton, and is thus an
interesting compound as a target for synthesis. The structure1a
was deduced by spectroscopic experiments, chemical trans-
formations and X-ray crystallography. We describe herein the
first total synthesis of (±)-hyperolactone A 8a by condensation
of two fragments, aldehyde 2 and lactone 4.
ii
Me
Me
O
O
O
5
O
6
iii
O
O
O
O
O
O
OH
OH
+
The aldol reaction of the lithium enolate of lactone 4, derived
from 3-furoic acid, with the aldehyde 2, derived from
2-methylbutanal (Scheme 1), afforded 5† in 81% yield (Scheme
2). The crude alcohol 5 was oxidized to furnish 6 (a mixture of
four diastereoisomers‡) by the Swern method in 92% yield.
O
O
O
O
7a
7b
iv
2
Attempted oxidation of
6 with MoO5·pyridine·HMPA
O1
O
3
+
(MoOPH)3 was unsuccessful, giving the undesired 7b only in
18% yield, while with Davis reagent4 a separable isomeric
mixture of 7a and 7b§ was obtained in 57% yield in a ratio of
2:3. A NOE was observed between the 9-methyl group and the
OH for the minor isomer 7a, but not for the major isomer.
On treatment of 7a with 3 m HCl in boiling THF to remove
the ketal protecting group (which strongly resisted hydrolysis),
a mixture of the final product 8a and its isomer 8b was obtained
in 85% yield in a ratio of 1:1, which was separated to give
(±)-hyperolactone 8a¶ as an oil.
9
5
O
O
8
6
O
O
O
O
8a Hyperolactone
8b
Scheme 2 Reagents and conditions: i, LDA, THF, 278 °C, 1 h, then
240 °C, 1.5 h, 81%; ii, DMSO, (COCl)2, CH2Cl2, Et3N, 278 °C, 10 min,
92%; iii, Davis reagent, 57%; iv, 6 m HCl, THF, reflux, 10 h, 85%
Footnotes and References
The advantages of this strategy are that it is short and
efficient, and provides a one-step construction of the spirolac-
tone by acid catalysis via deprotection, cyclization and
elimination.
* E-mail: takamasa@sci.osaka-cu.ac.jp
† Although a multitude of isomers are formed, in the light of the subsequent
steps this does not matter.
We are grateful to Professor M. Tada (Tokyo University of
Agriculture and Technology) for kindly providing a reference
spectra of Hyperolactone A and for useful comments.
‡ The relative proportion (2:2:2:1) was estimated from the carbonyl
absorptions: dC 197.1, 198.8, 201.4 and 202.2.
§ The diastereoselectivity was not improved, even in the case of a less bulky
electrophile such as the Davis reagent.
¶ Selected data [dH (400) MHz, CDCl3)] for 8a: 0.96 (3 H, t, J 7.3), 1.25 (3
H, d, J 7.3) 1.41 (3 H, s), 1.54–1.66 (1 H, m), 1.66–1.80 (1 H, m), 2.69 (1
H, tq, J 6.7), 4.04 (1 H, d, J 8.5), 4.89 (1 H, d, J 8.5), 5.24 (1 H, d, J 17.1),
5.28 (1 H, d, J 11.0), 5.37 (1 H, s), 5.93 (1 H, dd, J 11.0, 17.1). For 8b: 0.98
(3 H, t, J 7.3), 1.27 (3 H, d, J 7.3), 1.41 (3 H, s), 1.50–1.60 (1 H, m),
1.62–1.80 (1 H, m), 2.66 (1 H, tq, J 6.7), 4.04 (1 H, d, J 8.5), 4.89 (1 H, d,
J 8.5), 5.24 (1 H, d, J 17.1), 5.28 (1 H, d, J 11.0), 5.37 (1 H, s), 5.94 (1 H,
dd, J 11.0, 17.1). The 1H NMR spectrum of (±)-8a thus obtained was
identical with that of the natural product recorded by Tada et al. [ref.
1(a)].
OH
CHO
O
O
i
ii–iv
CO2Et
CHO
1
2
1 (a) M. Tada, M. Nagai, C. Okumura, Y. Osano and T. Matsuzaki, Chem.
Lett., 1989, 683; (b) Y. Aramaki, K. Chiba and M. Tada, Phytochemistry,
1995, 38, 1419.
2 T. Kinoshita, D. Ichinari and J. Sinya, J. Heterocycl. Chem., 1996, 33,
1313.
CO2H
CHO
Me
v
vi–viii
Me
O
O
O
O
3
4
3 E. Vedejs and S. Larsen, Org. Synth., 1990, Coll. Vol. VII, 277.
4 F. A. Davis and O. D. Stringer, J. Org. Chem., 1982, 47, 1774;
F. A. Davis, L. C. Vishwakarma, J. M. Billmers and J. Finn, J. Org.
Chem., 1984, 49, 3241.
Scheme 1 Reagents and conditions: i, Zn, BrCH2CO2Et, C6H6, reflux, 1.5
h, 75%; ii, CrO3, pyridine, CH2Cl2, room temp., 30 min, 83%; iii,
(CH2OH)2, TsOH, PhMe, reflux, 7 h, 39%; iv, DIBAL-H, PhMe, 278 °C,
10 min, 98%; v, ref. 2; vi, Ph3MeP+ Br2, BuLi, Et2O, reflux, 12 h; vii,
BuOH, TsOH, CH2Cl2; viii, CrO3, H2SO4, acetone, 45% over three steps
Received in Cambridge, UK, 16th June 1997; 7/04159D
Chem. Commun., 1997
1743

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