Diterpenic α- and β-hydroxybutanolides with antifeedant activity: Semisynthesis and absolute configuration

Article abstract of DOI:10.1016/S0040-4039(00)00227-6

Two series of ent-halimanolides (15,16-olides and 16,15-olides), analogues of biologically active diterpene lactones, were synthesized starting from ent-halimic acid methyl ester. The absolute configuration was determined by CD spectroscopy and corroborat

Full text of DOI:10.1016/S0040-4039(00)00227-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2553–2557
Diterpenic α- and β-hydroxybutanolides with antifeedant
activity: semisynthesis and absolute configuration†
I. S. Marcos,a,∗ J. L. Gonzalez,a M. J. Sexmero,a D. Díez,a P. Basabe,a D. J. Williams,b
M. S. J. Simmonds c and J. G. Urones a
aDepartamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5,
37008 Salamanca, Spain
bDepartment of Chemistry, Imperial College of Science Technology and Medicine, South Kensington, London SW7 2AY, UK
cJodrell Laboratory, Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3AB, UK
Received 5 January 2000; accepted 5 February 2000
Abstract
Two series of ent-halimanolides (15,16-olides and 16,15-olides), analogues of biologically active diterpene
lactones, were synthesized starting from ent-halimic acid methyl ester. The absolute configuration was determined
by CD spectroscopy and corroborated by X-ray analysis. Antifeedant testing has been carried out on these
compounds. © 2000 Elsevier Science Ltd. All rights reserved.
Strong biological activities have been reported for mono- or polycyclic molecules, diterpenes or sester-
terpenes, that possess a five-membered oxygenated ring with different functionalities.1 Ajugarin,2 a neo-
clerodane with a butenolide, is an antifeedant, aplyolide3 has anti-inflammatory activities, dysidiolide4
is the first naturally derived inhibitor of the cdc25A protein phosphatase and polauolide5 (an unsaturated
hemiacetal) has antimicrobial properties.
We decided to investigate the synthesis of different chiral α and β-hydroxybutenolides on the same
diterpene skeleton in order to determine the influence of the configuration on the biological activity.
∗
†
Corresponding author.
In respectful memory of the late Professor J. de Pascual Teresa.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00227-6
tetl 16507

2554
As a starting material the ent-halimic acid methyl ester6 1 was used. By selective photooxygenation
and hydroboration it was transformed into the triol 3. The selective protection of the hydroxy groups on
C-14 and C-15 or C-14 and C-16 as 1,3-dioxolane or 1,3-dioxane gave 4 and 10, respectively. These
compounds were oxidized to the corresponding acids 5 and 11, respectively, by treatment with PDC in
DMF. Finally, deprotection with TsOH in MeOH allowed the access to β-hydroxybutanolides, in a ratio
(27:33:20:20) 6–9 or α-hydroxybutanolides, ratio (22:22:28:28) 12–15, as indicated in Scheme 1.
Scheme 1. (a) Rose Bengal, hν, O2, then NaBH4; (b) BH3, THF, then H2O2/NaOH; (c) 2,2 DMP, CSA; (d) PDC, DMF; (e)
PhCHO, CSA; f) TsOH, MeOH

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The relative configuration of R, and of the hydroxy group on the lactone ring for 6 to 9, was established
by 1H NMR spectroscopy (Table 1). Taking account of the coupling constants of H–C14 and H–C15 it
was deduced that the more polar lactones 8 and 9 have a trans stereochemistry whilst the less polar
lactones 6 and 7 are cis.
Table 1
The absolute configuration was established by CD spectroscopy by applying the chirality rule of the
lactone ring established by Wolf, Legrand and Beecham.7 The more stable conformation for 9 is the one
with R and OH equatorial. The dihedral angle is negative and the Cotton effect is positive (∆ε218=+0.810)
so the configuration of 9 is 13S,14S. In the same manner, 8 (∆ε233=−0.020) will be 13R,14R. The
structure for 9 was corroborated by single crystal X-ray analysis.8 The absolute configuration for the
isomers 6 and 7 with the hydroxy group pseudo axial and the side chain pseudo equatorial was deduced
by the sign of the Cotton effect: negative for 6 (∆ε227=−0.582) so the configuration is 13R,14S, and
positive for 7 (∆ε222=+1.221) so the configuration is 13S,14R.
The relative configurations for the α-hydroxybutanolides 12–15 were established on the basis of the
1
coupling constants in the H NMR (Table 2) for H–C14 and H–C16, being cis for the side chain and
the hydroxy group on the lactone ring for 12 and 13 and trans for 14 and 15. The structure of 14 was
corroborated by a single crystal X-ray analysis.9 Their absolute configurations were again established
by CD: 12 (∆ε219=+2.162), 13S,14S; 13 (∆ε224=−0.841), 13R,14R; 14 (∆ε223=−1.717), 13S,14R and,
hence, 15, 13R,14S.
In order to check for antifeedant activity, lactone 20 was synthesized starting from 16 (Scheme 2).9
The treatment with LDA/TMSCl and ulterior oxidation with mCPBA gave 17 that was protected as its

2556
Table 2
MOM derivative 18. A Reformatsky10 reaction of ethyl bromoacetate and 18 gave the mixture (1:1) of
hydroxyesters, 19, which, after deprotection, led to the required hydroxylactones 20.
Scheme 2. (a) LDA/TMSCl, then mCPBA; (b) (MeO)2CH2/P2O5; (c) Zn–Cu/I2/BrCH2COOMe; (d) HCl, MeOH
Finally, compounds 6–9, 12–15 and 20 were tested for their antifeedant activity against larvae of
Spodoptera littoralis. The results of these bioassays are shown in Table 3.
Table 3
Effect of some neo-clerodane on the feeding behaviour of larvae of Spodoptera littoralis, antifeedant
index*
As can be deduced from Table 3, none of the β-hydroxybutanolides are antifeedants, α-
hydroxybutanolides 14 and 15 are weakly active and 20 is moderately so. Studies to increase the
activities are in progress.
In this paper, we have established, via CD spectroscopy, the absolute configurations of some butanoli-
des not anchored to rigid systems.

2557
Acknowledgements
Financial support for this work came from the Spanish CICYT (PB97-1323).The authors thanks Prof.
J. Trujillo and Dr. A. M. Lithgow for the CD and NMR spectra, respectively.
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