Synthesis of the proposed structure of fudecalone, an anticoccidial drimane terpenoid.

Article abstract of DOI:10.1021/ol990882a

[formula: see text] The proposed structure of fudecalone (1), an anticoccidial drimane sesquiterpene, was synthesized as a racemate in six steps starting from a known phthalide (5). Interestingly, our synthetic 1 showed conformation 1b, while the natural

Full text of DOI:10.1021/ol990882a

ORGANIC
LETTERS
1999
Vol. 1, No. 7
1079-1080
Synthesis of the Proposed Structure of
Fudecalone, an Anticoccidial Drimane
Terpenoid
Hidenori Watanabe,* Takeshi Furuuchi, Takahiro Yamaguchi, and
Takeshi Kitahara
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life
Sciences, The UniVersity of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
ashten@mail.ecc.u-tokyo.ac.jp
Received July 28, 1999
ABSTRACT
The proposed structure of fudecalone (1), an anticoccidial drimane sesquiterpene, was synthesized as a racemate in six steps starting from
a known phthalide (5). Interestingly, our synthetic 1 showed conformation 1b, while the natural one was reported as 1a, and the NMR spectral
data were not identical.
In 1995, Omura et al. isolated and identified a new drimane
sesquiterpene, fudecalone (1), from a culture broth of
Penicillium sp. FO-2030.1 It exhibited an anticoccidial
activity against monensin-resistant Eimeria tenella at 16 µM.
The structure was elucidated mainly by various NMR
experiments, and the conformation of 1 was reported to be
1a. Herein, we report a synthesis of the proposed structure
of 1. Our synthetic 1 presented the conformation 1b and
Scheme 1a
1
showed nonidentical H and 13C NMR specrta.
a (a) Dimethyl acetylenedicarboxylate, 180-200 °C (89%); (b)
LiAlH4, THF (99%); (c) concentrated HCl, Et2O, 0 °C; (d) Jones’
reagent, acetone; (e) aqueous NaOH, THF (72% in three steps).
Alder reaction of pyrone 2 with dimethyl acetylenedicar-
boxylate gave decarboxylated product 3.
Two ester groups of 3 were reduced, and HCl treatment
of the resulting diol gave 4 regioselectively. Jones oxidation
and successive base treatment caused lactone formation to
afford 5 in 63% yield over five steps from 2.
We started our synthesis from the known phthalide 5.2
As the reported procedure for the synthesis of 5 was lengthy
and complicated, we developed a simpler method for
multigram preparation of 5 as shown in Scheme 1. Diels-
(1) Tabata, N.; Tomoda, H.; Masuda, R.; Iwai, Y.; Omura, S. J. Antibiot.
1995, 48, 53-58.
(2) (a) Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1987, 231-235.
(b) Meldrum, A. N. J. Chem. Soc. 1911, 1712-1721.
Birch reduction of 5 with potassium in liquid ammonia
and homoprenylation of the resulting enolate gave 6 in 62%
yield (Scheme 2). Acid hydrolysis of the enol ether and
10.1021/ol990882a CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/14/1999

although the patterns of the peaks were quite similar to those
of natural fudecalone.1,4 The correctness of the structure of
our synthetic 1 was confirmed by oxidizing it with Dess-
Martin periodinane5 to the undoubted precursor 8 in 72%
yield. More interestingly, an NOE experiment revealed the
conformation of synthetic 1 to be 1b, which was different
from that of natural 1. Omura et al. reported the conformation
of natural fudecalone to be 1a from the results of the NOE
experiment.1 According to MM3 calculation, 1b′ is 2.1 kcal/
mol more stable than 1a and all our attempts of conforma-
tional isomerization of 1b or its derivatives to 1a resulted in
failure.
Scheme 2a
Two explanations are possible for this disagreement: (1)
Natural fudecalone is certainly the unstable conformer 1a,
but the five-membered hemiacetal ring restricts the flexibility
of the molecule and makes the energy barrier between 1a
and 1b′ extraordinarily high. Therefore, it cannot isomerize
to the more stable conformation 1b′. (2) The proposed
stereochemistries are incorrect and the real structure of
fudecalone is that shown in 13 or 14.
a (a) K, liquid NH3, t-BuOH, then LiBr, 5-iodo-2-methyl-2-
pentene, THF-HMPA (62%); (b) 3 N HCl, THF (46%); (c) LDA,
Ac2O, THF; (d) BF3(gas), CH2Cl2-H2O, rt (90% in two steps);
(e) DIBAL, CH2Cl2, -78 °C [91%(9) + 8%(10) from 8; 91% from
10]; (f) MnO2, CH2Cl2 (84%); (g). Dess-Martin periodinane,
CH2Cl2 (72%).
Building on these points of view, conformationally selec-
tive synthesis of 1a and stereoselective synthesis of 13 and
14 are in progress and will be reported in due course.
isomerization of the double bond afforded conjugated enone
in 46% yield along with a nonconjugated enone (24%), which
was then converted into enol acetate 7. The next step was
the key cyclization to form the tricyclic compound. When 7
was treated with BF3 in wet CH2Cl2, an axial attack of a
cationic side chain to the enol acetate took place and the
desired 8 was obtained as a sole product in 90% yield (in
two steps).3 The stereochemistry including its conformation
was confirmed as 8′ by NOE experiment and X-ray analysis.
For converting 8 into fudecalone, an unsaturated ketone
and a lactone carbonyl were reduced with 4 equiv of DIBAL
to give 9 in a maximum yield of 91%. This step was not
reproducible, and sometimes 10 was obtained as a major
product along with minor 9 (66% + 33%). Hydroxy lactone
10 could be converted into 9 in 91% yield by the further
reduction with DIBAL. Allylic alcohol 9 was selectively
reoxidized with MnO2, and 1 was obtained as an inseparable
crystalline diastereomeric mixture with a broad melting point
(162-173 °C, after recrystallization) in 84% yield. The
overall yield of 1 was 20% from 5 (in six steps) and 12%
from 2 (in 11 steps).
Acknowledgment. We thank Prof. S. Omura and Dr. N.
Tabata of the Kitasato Institute for the generous gift of the
spectral data of natural fudecalone. We also thank Dr. M.
Kido and Mr. M. Bando of Otsuka Pharmaceutical Co., Ltd.,
for X-ray analysis of 8. This work was supported by a Grant-
in-Aid for Scientific Research from Japanese Ministry of
Education, Science, Culture and Sports.
OL990882A
(4) In CDCl3, the hemiacetal of the synthetic 1 equilibrated to an R/â )
1:3 mixture: 1H NMR (500 MHz, in CDCl3) major isomer, δ 5.90 (br m,
1H, H-5), 4.94 (s, 1H, H-1), 4.33 (t, J ) 9.0 Hz, 1H, H-3), 4.09 (dd, J )
9.0, 3.0 Hz, 1H, H-3), 2.72 (br d, J ) 9.0 Hz, 1H, H-3a), 2.22 (s, 1H,
H-6a), 1.91 (t, J ) 1.0 Hz, 3H, H-11), 1.71 (m, 1H, H-10), 1.50-1.70 (m,
2H, H2-9), 1.46 (m, 1H, H-8), 1.30 (m, 1H, H-8), 1.24 (m, 1H, H-10), 1.05
(s, 3H, H-13), 0.76 (s, 3H, H-12); minor isomer, δ 5.90 (br m, J ) 1.0 Hz,
1H, H-5), 4.98 (s, 1H, H-1), 4.33 (dd, J ) 9.0, 7.0 Hz, 1H, H-3), 3.97 (br
d, J ) 9.0 Hz, 1H, H-3), 2.81 (br d, J ) 7.0 Hz, 1H, H-3a), 2.14 (s, 1H,
H-6a), 1.95 (t, J ) 1.0 Hz, 3H, H-11), 1.01 (s, 3H, H-13), 0.79 (s, 3H,
H-12); 13C NMR (125 MHz, in CDCl3) major isomer, δ 200.80, 156.53,
128.47, 107.38, 70.00, 54.46, 48.44, 44.10, 41.54, 34.73, 33.40, 31.32, 24.60,
22.29, 18.16; minor isomer, δ 201.00, 158.84, 128.47, 102.71, 68.51, 55.46,
46.68, 46.20, 41.26, 33.79, 31.48, 25.88, 24.09, 22.01, 18.37.
Contrary to our expectation, however, the 1H and 13C NMR
spectra of synthetic 1 showed different chemical shifts
(5) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(c) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (d) Meyer, S. D.;
Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552.
(3) Fairlie, J. C.; Hodgson, G. L.; Money, T. J. Chem. Soc., Perkin Trans.
1 1973, 2109-2112.
1080
Org. Lett., Vol. 1, No. 7, 1999