Total synthesis of (±)-arohynapene B

Article abstract of DOI:10.1246/cl.2005.352

The total synthesis of (±)-arohynapene B, an anticoccidial agent isolated from the fermentation broth of a fungal strain, has been achieved. The tetrahydronaphthalene ring was constructed by the Diels-Alder reaction between dimethyl acetylenedicarboxylate

Full text of DOI:10.1246/cl.2005.352

352
Chemistry Letters Vol.34, No.3 (2005)
Total Synthesis of (Æ)-Arohynapene B
Hideyuki Sugimuraꢀ and Yuki Uchida
Faculty of Education and Human Sciences, Yokohama National University,
79-2, Tokiwadai, Hodogaya-ku, Yokohama 240-8501
(Received December 2, 2004; CL-041474)
The total synthesis of (ꢁ)-arohynapene B, an anticoccidial
tively hydrogenated in the presence of 10% Pd/C under atmo-
spheric H2 in benzene to give cis-3,5-dimethylcyclohexanone
26 (cis:trans = 19:1 estimated by 13C NMR). The treatment of
2 with ethynylmagnesium bromide in THF, followed by acetyla-
tion, provided the propargyl acetate derivative 3 in 72% yield.
The acetate 3 was converted to 1,3-dienyl acetate 4 by treatment
with a catalytic amount of silver trifluoroacetate in refluxing
benzene in 73% isolated yield after silica gel chromatography.5
The Diels–Alder reaction of 4 was best accomplished using three
equivalents of dimethyl acetylenedicarboxylate in toluene under
reflux for four days, and then treating with DBN as a base for
completion of the acetic acid elimination. Numerous reaction
conditions were investigated in order to improve the product
yield (solvent, Lewis acid catalyst, reaction temperature, base,
etc.), but none proved to be better than the above conditions.
With the tetrahydronaphthalene skeleton in hand, we next
focused on the introduction of the dienylcarboxylic acid side
chain at the correct position. After reduction of the diester 5 with
LiAlH4, selective protection of the hydroxymethyl group at C-2
in the diol 67 was investigated. When the diol 6 was treated with
t-butyldimethylsilyl chloride (TBSCl) and triethylamine–
DMAP(cat.) as base in dichloromethane, the desired TBS ether
7 was obtained in 47% yield along with the regioisomeric TBS
ether 70 (13%), bis-TBS ether 700 (12%) and recovery of 6
(17%). In contrast, a similar reaction using two equivalents of
imidazole as the base in DMF gave the TBS ether 7, bis-TBS
ether 700 and the starting diol 6 in 48, 14 and 21% yields, respec-
tively, without the production of the TBS ether 70. Although the
yields of the desired product obtained from these two reactions
are almost the same, the latter condition is more convenient be-
cause it can avoid difficulties in the separation of the regioiso-
meric by-product 70 by column chromatography. The TBS-ether
70 and bis-TBS ether 700 were reused after converting to the diol 6
by treatment with tetrabutylammonium fluoride. Oxidation of
the remaining hydroxyl group in 7 with PCC provided the alde-
hyde 8 in 79% yield. The attempt to introduce the dienylcarbox-
ylate moiety directly to 8 using (EtO)2P(O)CH2CH=CHCO2Et/
NaH failed because the reaction was very sluggish, and the yield
of 11 was only 9%. Therefore, we next tried a stepwise approach
for the installation of the side chain. The Horner–Wadsworth–
Emmons olefination using (EtO)2P(O)CH2CO2Et/NaH in dime-
thoxyethane gave the unsaturated ester 9 in 91% yield. The ester
9 was reduced to the allyl alcohol 10 by DIBAL in 97% yield.
The oxidation of 10 with manganese dioxide afforded an unsat-
urated aldehyde, which was subsequently subjected to the sec-
ond Horner–Wadsworth–Emmons olefination to provide the
fully protected arohynapene B (11).
agent isolated from the fermentation broth of a fungal strain,
has been achieved. The tetrahydronaphthalene ring was con-
structed by the Diels–Alder reaction between dimethyl acetyle-
nedicarboxylate and the 1-(ꢀ-acetoxyvinyl)cyclohexene deriva-
tive, which was prepared from 3,5-dimethylcyclohexanone via
the Agþ-catalyzed rearrangement of the propargylic acetate
derivative. The introduction of the dienylcarboxylic acid side
chain was accomplished by the Horner–Wadsworth–Emmons
olefination repeatedly utilizing ethyl diethylphosphonoacetate.
Finally, careful removal of the protecting groups led to (ꢁ)-aro-
hynapene B.
Arohynapenes are new anticoccidial agents, isolated from
the fermentation broth of the Penicillium sp. FO-2295 strain,
and their structures have been proposed as shown in Figure 1.1
More recently, another natural product with a structure analo-
gous to arohynapene B, tanzawaic acid A, has been isolated from
Penicillium citrinum as an inhibitor of superoxide anion produc-
tion,2 of which the absolute structure has been elucidated as
shown in Figure 1 by an asymmetric total synthesis.3 Although
the stereochemistry of the arohynapenes is still unclear, from a
comparison between the reported spectral data of tanzawaic acid
A and those of arohynapene B, we deduced that the relative ster-
eochemistry of the two methyl substituents in arohynapene B
will be a cis relationship. Herein, we report the first total synthe-
sis of the racemic arohynapene B in a straightforward manner
starting from cis-3,5-dimethylcyclohexanone, which also led to
the assignment of its relative stereochemistry.
CH
3
OH
HO
H C
CO H
CO H
2
2
CH
H C
3
CH
3
3
3
Arohynapene A
Arohynapene B
CH
3
CO H
2
H C
3
CH
3
Tanzawaic Acid A
Figure 1.
Our approach to the tetrahydronaphthalene ring of arohyna-
pene B involves a Diels–Alder reaction4 between dimethyl ace-
tylenedicarboxylate and 3,5-dimethyl-1-(ꢀ-acetoxyvinyl)cyclo-
hexene, which could be prepared from the propargylic acetate
derivative according to a literature procedure.5 These results
are summarized in Scheme 1. To start with, commercially avail-
able (ꢁ)-3,5-dimethyl-2-cyclohexen-1-one (1) was stereoselec-
In the final steps, deprotection of the TBS ether and ethyl es-
ter, the order of removal of the protecting groups is crucial for
obtaining a high yield of the product 12. If the TBS group is first
removed and then the ethyl ester is hydrolyzed under basic con-
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.3 (2005)
353
OAc
CO Me
O
O
2
AcO
a
b, c
d
e
CO Me
2
( )-1
2
3
4
5
3
2
1
2
4
OH
OH
OR
OR
OTBDMS
f
g
i
1
5
CHO
6
8
7
1
2
7: R =TBDMS, R =H
6
8
1
2
h
7': R =H, R =TBDMS
6
1
2
7": R =R =TBDMS
OTBDMS
CO Et
OTBDMS
OTBDMS
OH
j
k
l,m
CO Et
2
2
11
9
10
13
OH
O
n
CO H
2
CO H
12
( )-Arohynapene B
2
Scheme 1. Reagents and conditions: (a) H2, 10% Pd/C, benzene, quant. (cis:trans = 19:1) (b) HCꢃCMgBr, THF (c) Ac2O,
DMAP(cat.), pyridine, 72% from 2 (d) CF3CO2Ag(cat.), benzene, reflux, 73% (e) MeO2CCꢃCCO2Me, toluene, reflux, then DBN,
reflux, 42% (f) LiAlH4, Et2O, reflux, 59% (g) TBDMSCl, imidazole, DMF, 48% (h) Bu4NF, THF (i) PCC, CH2Cl2, 79% (j)
(EtO)2P(O)CH2CO2Et, NaH, DME, 91% (k) DIBAL, CH2Cl2, 97% (l) MnO2, benzene (m) (EtO)2P(O)CH2CO2Et, NaH, DME,
84% from 10 (n) LiOH, THF–MeOH–H2O, then Dowex 50W (Hþ form), 50 ꢂC, quant.
ditions, the intramolecular conjugate addition of the hydroxyl
group to the ꢁ-position of the dienylcarboxylate side chain par-
tially occurs to give the dihydroisobenzofuran derivative 13, re-
sulting in a decrease of the yield of 12. This problem, however,
could be solved by the following procedure: the ethyl ester was
first hydrolyzed under basic conditions (LiOH/THF–MeOH–
H2O), and then the reaction mixture was neutralized with ion ex-
change resin (DOWEX 50W Hþ-form). Furthermore, the addi-
tion of excess resin to the reaction mixture, followed by warming
of the mixture to 50 ꢂC led to (ꢁ)-arohynapene B 12 in quanti-
tative yield. The 1H and 13C NMR data of the synthetic sample8
were identical to those reported in the literature.1 Hence, the rel-
ative stereochemistry of the two methyl groups in arohynapene
B could be assigned to be cis.
In summary, we have achieved the total synthesis of (ꢁ)-ar-
ohynapene B (12) from the readily available cis-3,5-dimethylcy-
clohexanone (2) in 12 steps. This route is short and concise, fea-
turing the direct construction of the tetrahydronaphthalene ring
by the Diels–Alder reaction. The resolution of each enantiomer
as well as the elucidation of the absolute configuration of the nat-
ural product is currently underway in our laboratory.
Arimoto, T. Okamura, and D. Uemura, Chem. Lett., 1997, 885.
H. Arimoto, K. Nishimura, M. Kuramoto, and D. Uemura,
Tetrahedron Lett., 39, 9513 (1998).
R. K. Hill and R. M. Carlson, Tetrahedron Lett., 5, 1157 (1964).
R. C. Cookson, M. C. Cramp, and P. J. Parsons, J. Chem. Soc.,
Chem. Commun., 1980, 197.
3
4
5
6
7
See ref. 20 in the following literature, W. S. Mahoney,
D. M. Brestensky, and J. M. Stryker, J. Am. Chem. Soc., 110,
291 (1988).
For the cis-isomer of 6: 1H NMR (CDCl3, 270 MHz) ꢁ 1.05 (d,
3H, J ¼ 6:6 Hz, 6-CH3), 1.24 (d, 3H, J ¼ 7:3 Hz, 8-CH3),
1.08–1.15 (m, 1H, H-7), 1.59–1.65 (m, 1H, H-6), 2.16–2.29
(m, 1H, H-7), 2.37 (dd, 1H, J ¼ 11:9, 15.2 Hz, H-5), 2.63
(ddd, 1H, J ¼ 2:6, 3.3, 15.2 Hz, H-5), 3.36 (dq, 1H, J ¼ 6:6,
7.3 Hz, H-8), 4.64 (d, 1H, J ¼ 11:9 Hz, 1-CH2), 4.65 (d, 1H,
J ¼ 11:9 Hz, 1-CH2), 4.72 (d, 1H, J ¼ 11:9 Hz, 2-CH2), 4.74
(d, 1H, J ¼ 11:9 Hz, 2-CH2), 6.99 (d, 1H, J ¼ 7:9 Hz, H-4),
7.06 (d, 1H, J ¼ 7:9 Hz, H-3).
8
Spectral data of the synthetic arohynapene B (12) 1H NMR
(CDCl3, 270 MHz) ꢁ 1.05 (d, 3H, J ¼ 6:6 Hz), 1.13 (d, 3H,
J ¼ 6:6 Hz), 1.22–1.28 (m, 2H), 2.10–2.19 (m, 1H), 2.33–
2.42 (m, 1H), 2.60–2.68 (m, 1H), 3.16–3.25 (m, 1H), 4.62 (s,
2H), 5.94 (d, 1H, J ¼ 15:8 Hz), 6.56 (dd, 1H, J ¼ 11:2,
15.8 Hz), 7.03 (d, 1H, J ¼ 7:9 Hz), 7.13 (d, 1H, J ¼ 15:8 Hz),
7.20–7.30 (m, 1H), 7.49 (dd, 1H, J ¼ 11:2, 15.2 Hz); 13C NMR
(CDCl3, 100 MHz) ꢁ 22.2, 24.2, 29.6, 30.8, 39.6, 41.4, 63.1,
121.0, 125.8, 128.5, 131.5, 135.0, 136.2, 138.2, 139.0, 140.8,
145.5, 169.4.
We thank the Asahi Kasei Pharma Corporation for their
financial support.
References and Notes
1
R. Masuma, N. Tabata, H. Tomoda, K. Haneda, Y. Iwai, and S.
Omura, J. Antibiot., 47, 46 (1994).
M. Kuramoto, K. Yamada, M. Shikano, K. Yazawa, H.
2
Published on the web (Advance View) February 5, 2005; DOI 10.1246/cl.2005.352