Stereoselective total syntheses of (±)-arthrinone and related natural compounds

Article abstract of DOI:10.1016/S0040-4039(00)01786-X

The first total syntheses of (±)-arthrinone, (±)-1-dehydroxyarthrinone, and (±)-3a,9a-deoxy-3a-hydroxyl-dehydroxyarthrinone, antifungal metabolites from the coprophilous fungus Cercophora sordarioides, were accomplished in a stereoselective manner. The ring systems of these metabolites, which were rare among natural products, were efficiently and diastereoselectively assembled using the [2,3]Wittig rearrangement and Diels-Alder reaction as the key steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01786-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10013–10017
Stereoselective total syntheses of ( )-arthrinone and related
natural compounds
Masahiko Uchiyama,* Yoshiyuki Kimura and Akihiro Ohta
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji,
Tokyo 192-0392, Japan
Received 31 August 2000; revised 4 October 2000; accepted 6 October 2000
Abstract
The first total syntheses of ( )-arthrinone, ( )-1-dehydroxyarthrinone, and ( )-3a,9a-deoxy-3a-hydroxy-
1-dehydroxyarthrinone, antifungal metabolites from the coprophilous fungus Cercophora sordarioides,
were accomplished in a stereoselective manner. The ring systems of these metabolites, which were rare
among natural products, were efficiently and diastereoselectively assembled using the [2,3]Wittig rear-
rangement and Diels–Alder reaction as the key steps. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: antifungal metabolites; oxyselenenylation; [2,3]Wittig rearrangement; Diels–Alder reaction.
Arthrinone (1) was originally isolated in 1994 as an antifungal metabolite from Arthrinium sp.
FA 1744, and its relative stereostructure was confirmed by X-ray crystallographic analysis.1a In
1997 it was also isolated from coprophilous fungus Cercophora sordarioides along with three
structurally related compounds:1b 1-dehydroxyarthrinone (2), 3a,9a-deoxy-3a-hydroxy-1-dehy-
droxyarthrinone (3), and cerdarin (4), some of which exhibited anti-Candida and antibacterial
activity. Compounds 1, 2, and 3 have unique structural features, namely, the epoxynaphtho[2,3-
c]furan ring system in a semiquinone form, which is rare among natural products. But to date,
the absolute stereochemistries of them were not confirmed unambiguously. Only the absolute
1
stereochemistry at C-4 of 2 was assigned by H NMR analyses of the corresponding (R)- and
(S)-2-phenylbutyric acid monoesters (Helmchen’s method), while every other stereochemistry
was proposed as shown in Fig. 1 by assuming the biosynthetic pathway of the resemblance
between 1, 2, and 3, and by considering NMR similarities. The absolute stereochemistry at C-3
of 4 was not elucidated, moreover, as for C-3a of 3, even its relative stereochemistry remains
undefined. Such a situation prompted us to undertake their asymmetric syntheses. In this paper,
we report the stereoselective total syntheses of ( )-1, ( )-2, and ( )-3 as the preliminary study
toward their asymmetric syntheses.
* Corresponding author. Tel: +81-426-76-3037; fax: +81-426-76-3040; e-mail: uchiyama@ps.toyaku.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01786-X

10014
OH
O
OH
O
OH
O
OH
O
9
OH
H
8
8
8
8
1
1
8a
1
8a
8a
9a
3a
1
9a
3a
8a
9a
3a
7
9
9
7
6
7
9
4
7
6
9a
O
3a
O
O
O
O
O
6
6
10
10
10
CH3O
10
CH3O
4
4
4
3
4a
4a
4a
4a
CH3O
CH3O
3
3
OH3
5
5
5
5
OCH3
O
OH
Arthrinone (1)
OH
1-Dehydroxyarthrinone (2)
11
OH
Cerdarin (4)
3a,9a-Deoxy-3a-hydroxy-
1-dehydroxyarthrinone (3)
Figure 1.
Our syntheses are illustrated in Schemes 1 and 2. As the starting material we used commer-
cially available 2,3-dihydrofuran, which was transformed to 6 by the oxyselenenylation–oxida-
tive deselenenylation sequence. Compound 6 was diastereoselectively converted to alcohol 7
using the [2,3]Wittig rearrangement reported by Nakai and co-workers.2,3
SePh
TMS
TMS
c
TMS
O
O
O
O
a
b
d
H
OH
H
OR
O
O
O
5
8 : R = H
6
7
e
OH
O
9 : R = TBDPS
EtO2C
i
EtO2C
EtO2C
f
g
h
O
O
O
TMSO
OMe
H
H
H
OTBDPS
OTBDPS
OTBDPS
13
12
10
11
OH
X
OR
TIPSO
O
TIPSO
TIPSO
OH
O
O
O
SPh
O
CO2Et
k, l
m
o
O
O
O
O
MeO
MeO
MeO
MeO
H
H
H
OTBDPS
OTBDPS
17 : X = SPh
18a,b : X = S(O)Ph
OTBDPS
OTBDPS
19
16
14 : R = H
j
n
15 : R = TIPS
HO
OH
O
HO
O
O
TIPSO
OH
TIPSO
OH
O
u
p
q
t
OH
OTBDPS
OH
OH
OH
OR1
OR2
OTBDPS
MeO
MeO
MeO
MeO
OTBDPS
OTBDPS
v
OTBDPS
OTBDPS
26
20
25
21 : R1 = R2 = H
22 : R1 = TBS, R2 = H
23 : R1 = R2 = TBS
r
s
(±)-Arthrinone (1)
24 : R1 = TBS, R2 = TBDPS
Scheme 1. Reagents and conditions: (a) PhSeCl, CH2Cl2, −78°C; then 3-trimethylsilyl-2-propyn-1-ol, −78“−50°C,
94%; (b) 30% H2O2, NaHCO3, AcOEt, THF, 0°C“rt, 86%; (c) n-BuLi, THF, −78°C, 95%; (d) TBAF, THF, 0°C“rt,
98%; (e) TBDPSCl, imidazole, DMF, rt, 85%; (f) n-BuLi, THF, −78°C; then ClCO2Et, −78°C“rt, 96%; (g) AcOH,
,
THF, H2O, rt, 93%; (h) PCC, MS 4 A, CH2Cl2, 0°C“rt, 95%; (i) 13, 160°C; then THF, 5% HCl, rt, 81%; (j) TIPSCl,
imidazole, DMF, rt, 100%; (k) NaHMDS, THF, −78°C; (l) NaH, THF, 0°C; then PhSCl, 87% from 15; (m)
Zn(BH4)2, CH2Cl2, 0°C, 83%; (n) mCPBA, CH2Cl2, 0°C, (18a: 81%, 18b: 9%); (o) P(OMe)3, toluene, reflux, 89% from
18a, 76% from 18b; (p) DIBAL-H, CH2Cl2, −78°C; then NaBH4, MeOH, 0°C, 77%; (q) mCPBA, CH2Cl2, phosphate
buffer (pH 7.9), 0°C“rt, 72%; (r) TBSOTf, pyridine, THF, −60°C, (22: 78%, 23: 12%); (s) TBDPSCl, imidazole,
,
DMF, rt, 91%; (t) 5% NaOH in EtOH, THF, rt, 61%; (u) MnO2, acetone, rt, 91%; (v) cat. TPAP, NMO, MS 4 A,
CH2Cl2, rt; then TBAF, AcOH, THF, rt, 73%

10015
HO
O
O
HO
O
HO
OH
O
TIPSO
OH
O
d
b
c
a
OTBS
OTs
22
O
O
O
O
MeO
MeO
MeO
MeO
OTBDPS
OH
2
OTBDPS
27
28
29
OTBDPS
O
e
HO
HO
O
f
O
O
MeO
MeO
OH
OTBDPS
OH
OH
3
30
Scheme 2. Reagents and conditions: (a) p-TsCl, DMAP, Et3N, CH2Cl2, rt, 100%; (b) 5% NaOH in EtOH, THF, rt;
then DMSO, H2O, 90°C, 63%; (c) MnO2, acetone, rt, 100%; (d) TBAF, AcOH, THF, rt, 74%; (e) NaTeH, EtOH,
THF, 0°C, 77%; (f) TBAF, AcOH, THF, rt, 87%
We next set about constructing the aromatic ring by the Diels–Alder reaction. The first
requirement was incorporating an ethoxycarbonyl group into the alkyne terminus. This group
was presumed to activate the CꢀC triple bond as dienophile, and to be a source of C-9 in the
target compounds. Thus 7 was converted to 10 in three straightforward steps. Direct oxidation
of 10 with PCC gave lactone 12; however, it was very slow and inefficient. Alternatively, 12 was
smoothly obtained in high yield in two steps via lactol 11. With the dienophile 12 in hand, we
attempted to react it with a few oxygenated butadienes reported in the literature.4 Although
some dienes afforded the corresponding aromatic compounds by the Diels–Alder reaction and
subsequent hydrolytic workup, the resultant aromatic compounds needed to be transformed to
14 by additional steps. Thus, in order to synthesize 14 directly and efficiently from 12, we
prepared a novel diene 135 from commercially available 4,4-dimethyl-1,3-cyclohexanedione in
two steps. Fortunately, the Diels–Alder reaction of diene 13 with 12 proceeded successfully,
accompanied by cycloreversion. The crude reaction mixture was exposed to the hydrolytic
conditions to provide the desired phenolic compound 146 in 81% yield as the sole regioisomer.
Compound 14 is a key intermediate because it has all carbon atoms and functionalities requisite
for the construction of the target compounds, and, besides, the protected secondary hydroxy
group at the benzylic position is presumed to act as a stereodirecting group for the introduction
of the other stereochemistries in the target molecules.
The next task was to construct the cyclohexane ring. The phenolic hydroxy group in 14 was
protected with TIPS group to give 15, which was subjected to the intramolecular Dieckmann
condensation. A cyclized product was obtained, but, as it was not stable, it was directly
converted to 16. The stereochemistry at the ring junction of 16 was initially assigned on the basis
of NOESY correlation, and subsequently confirmed by the syn-elimination of sulfoxide 18
affording olefin 19. The reason for the introduction of a sulfenyl group was to create
unsaturation for the subsequent epoxidation; however, direct conversion of 16 into olefin was
presumed to be impossible because of the easy aromatization of the resultant olefin. Therefore,
16 was temporarily reduced with zinc borohydride7 to give alcohol 17,6 whose configuration was
assigned on the basis of NOESY correlation. Oxidation of 17 with mCPBA gave sulfoxides 18a
and 18b, epimers at the sulfur atom, in 81 and 9% yield, respectively. Compounds 18a and 18b
were refluxed separately in toluene to provide the desired olefin 19 in 89 and 76% yield,
respectively.

10016
The next phase of our syntheses was a stereoselective epoxidation of 19. Since 19 was an
a,b-unsaturated lactone, its epoxidation was first attempted by using alkaline hydrogen peroxide
and t-butyl hydroperoxide. However, the aromatization by dehydration of 19 easily took place
under these conditions; therefore, the desired epoxide was not obtained. Next we attempted the
epoxidation with electrophilic epoxidizing agents (e.g. peroxyacids, dioxiranes); however, 19
utterly resisted epoxidation. The poor reactivity of 19 towards electrophilic epoxidizing agents
was due to the carbonyl group which conjugated with the CꢀC double bond. Therefore, 19 was
successively reduced with diisobutylaluminium hydride (DIBAL-H)8 and NaBH4 to give triol 20,
whose epoxidation with mCPBA in CH2Cl2 in the presence of the phosphate buffer (pH 7.9)9
provided the epoxide 216 as a single stereoisomer. The stereochemistry of the epoxy moiety in
21 was uncertain at this stage, although we expected that mCPBA would have reacted with 19
from the opposite side to the bulky TBDPS group.
We proceeded to the next task, reconstruction of the tetrahydrofuran ring. It was performed
by the following steps: (i) selective mono-silylation of 21 with TBS group; (ii) protection of the
other primary hydroxy group with TBDPS; (iii) selective removal of TIPS and TBS groups; (iv)
oxidation of the hydroxy group at benzylic position with MnO2; (v) tetra-n-propylammonium
perruthenate (TPAP) oxidation10 of the primary hydroxy group; (vi) removal of two TBDPS
groups to give a yellowish compound. It exhibited identical properties with those reported for
the natural product1a (1H and 13C NMR, and IR). Thus, the total synthesis of ( )-arthrinone (1)
was achieved, and it revealed the stereochemistry of epoxide 21.
The other target compounds, 2 and 3, were synthesized from 22 as shown in Scheme 2. The
primary hydroxy group of 22 was tosylated selectively by a conventional procedure to give 27
quantitatively. Direct conversion of 27 to 28 by selective removal of TIPS and TBS groups and
subsequent cyclization was attempted using the same method as with 24 (Scheme 1). However,
the yield of 28 was very low. This poor result seemed to be due to the long reaction time, which
was required for complete removal of the TBS group of 27. Therefore, we took an alternative
two-step sequential method: tosylate 27 was treated with 5% ethanolic NaOH until 27 was not
detected by TLC analysis to give the mono-desilylated compound, whose TBS group remained,
along with 28. A mixture of the crude products was heated in wet DMSO at 90°C11 to afford
28 in moderate yield from 27. Oxidation of 28 with MnO2 afforded 29 quantitatively, which was
then desilylated to provide ( )-dehydroxyarthrinone (2). On the other hand, treatment of 29
with sodium hydrogen telluride12 was followed by desilylation to yield ( )-3a,9a-deoxy-3a-
hydroxy-1-dehydroxyarthrinone (3). Synthetic 2 and 3 were identified by comparing their
spectral data with those of the natural products1b (1H and 13C NMR, and MS).
Thus, we have accomplished the first total syntheses of ( )-arthrinone (1), ( )-1-dehydrox-
yarthrinone (2), and ( )-3a,9a-deoxy-3a-hydroxy-1-dehydroxyarthrinone (3) in a stereocon-
trolled manner. These syntheses unambiguously confirmed the relative stereochemistries of 2 and
3. The asymmetric syntheses of 1–3 are now in progress.
References
1. (a) Qian-Cutrone, J.; Gao, Q.; Huang, S.; Klohr, S. E.; Veitch, J. A.; Shu, Y.-Z. J. Nat. Prod. 1994, 57,
1656–1660. (b) Whyte, A. C.; Gloer, K. B.; Gloer, J. B.; Koster, B.; Malloch, D. Can. J. Chem. 1997, 75,
768–772.
2. Tomooka, K.; Watanabe, M.; Nakai, T. Tetrahedron Lett. 1990, 31, 7353–7354.

10017
3. This reaction is helpful for our final goal, the asymmetric syntheses of 1–4, because recently we found that the
asymmetric oxyselenenylation of 2,3-dihydrofuran and subsequent oxidation afforded 6 in an enantioselective
manner, which could give an optically active alcohol 7 by this rearrangement.
4. The dienes subjected to Diels–Alder reaction with 12 was as follows. (a) 1,1-Dimethoxy-3-trimethylsiloxy-1,3-
butadiene: Banville, J.; Brassard, P. J. Chem. Soc., Perkin Trans. 1 1976, 1852–1856. (b) 1,3-Bis(trimethylsiloxy)-
5,5-dimethylcyclohexa-1,3-diene: Ibuka, T.; Mori, Y.; Aoyama, T.; Inubushi, Y. Chem. Pharm. Bull. 1978, 26,
456–465. (c) 1,3-Dimethoxy-1-trimethylsiloxy-1,3-butadiene: Savard, J.; Brassard, P. Tetrahedron 1984, 40,
3455–3464. Only 1,3-dimethoxy-1-trimethylsiloxy-1,3-butadiene did not react with 12.
5. Diene 13 was prepared in the following way: 4,4-dimethyl-1,3-cyclohexanedione was treated with MeOH
containing a catalytic amount of HCl to afford 6,6-dimethyl-3-methoxy-2-cyclohexenone in 65% yield. It was
converted to 13 by treatment with LDA in THF at −78°C followed by quenching with TMSCl in 83% yield.
6. All new compounds gave satisfactory spectroscopic and analytical data. Representative data for selected
1
compounds; 14: IR (CHCl3): 1770, 1650 cm−1. H NMR (CDCl3) l 1.04 (9H, s), 1.09 (3H, t, J=7.2 Hz), 2.15
(1H, dd, J=9.0, 17.6 Hz), 2.27 (1H, dd, J=8.6, 17.6 Hz), 2.83 (1H, m), 3.79 (3H, s), 4.06–4.24 (3H, m), 4.40 (1H,
dd, J=7.5, 9.1 Hz), 5.81 (1H, d, J=4.5 Hz), 6.36 (1H, d, J=2.7 Hz), 6.89 (1H, d, J=2.7 Hz), 7.23–7.28 (2H, m),
7.34–7.47 (6H, m), 7.58–7.61 (2H, m), 11.62 (1H, s). Anal. calcd for C31H36O7Si: C, 67.86; H, 6.61. Found: C,
67.59; H, 6.55. 17: IR (CHCl3): 3460, 1760 cm−1. 1H NMR (CDCl3) l 1.06 (9H, s), 1.07 (3H, s), 1.10 (9H, s), 1.12
(6H, s), 1.24–1.36 (3H, m), 3.11 (1H, ddd, J=1.8, 3.7, 9.6 Hz), 3.21 (1H, dd, J=3.7, 9.6 Hz), 3.58 (3H, s), 3.67
(1H, t, J=9.6 Hz), 4.38 (1H, d, J=1.8 Hz), 4.43 (1H, d, J=12.4 Hz), 5.30 (1H, d, J=12.4 Hz), 5.86 (1H, d,
J=2.3 Hz), 6.35 (1H, d, J=2.3 Hz), 7.30–7.55 (11H, m), 7.70–7.73 (2H, m), 7.81–7.84 (2H, m). Anal. calcd for
1
C44H56O6SSi2: C, 68.71; H, 7.34. Found: C, 68.49; H, 7.45. 21: IR (CHCl3): 3590, 3490 cm−1. H NMR (CDCl3)
l 0.96 (9H, s), 1.14 (3H, s), 1.15 (3H, s), 1.16 (6H, s), 1.18 (6H, s), 1.29–1.41 (3H, m), 1.70 (1H, br-s), 2.75 (1H,
br-s), 2.94 (1H, d, J=10.9 Hz), 3.44 (3H, s), 3.89 (1H, d, J=12.8 Hz), 4.15 (1H, br-d, J=12.1 Hz), 4.23 (1H,
br-d, J=12.1 Hz), 4.25 (1H, br-d, J=12.8 Hz), 5.07 (1H, s), 5.58 (1H, d, J=10.9 Hz), 5.76 (1H, d, J=2.3 Hz),
6.37 (1H, d, J=2.3 Hz), 7.21–7.31 (4H, m), 7.35–7.41 (1H, m), 7.43–7.53 (3H, m), 7.75–7.78 (2H, m). Anal. calcd
for C38H54O7Si2: C, 67.22; H, 8.02. Found: C, 66.85; H, 8.07.
7. Reduction of 16 with other reducing agents, such as NaBH4, Ca(BH4)2, and n-Bu4NBH4, gave 17; however, the
desulfenylated by-product was also obtained. Zn(BH4)2 gave the best result.
8. The half-reduction of 19 with DIBAL-H afforded the corresponding lactol, but its epoxidation was fruitless.
9. Imuta, M.; Ziffer, H. J. Org. Chem. 1979, 44, 1351–1352.
10. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639–666.
11. Maiti, G.; Roy, S. C. Tetrahedron Lett. 1997, 38, 495–498.
12. Osuka, A.; Taka-oka, K.; Suzuki, H. Chem. Lett. 1984, 271–272.
.
.