Total synthesis of dehydroaltenusin

Article abstract of DOI:10.1016/S0040-4039(03)00072-8

First total synthesis of dehydroaltenusin, a natural enzyme inhibitor, is described. The key step involves Suzuki-couplig reaction of aryl triflate prepared from 2,4,6-trihydroxy benzoic acid with a catechol-derived boronic acid. The synthetic sample was

Full text of DOI:10.1016/S0040-4039(03)00072-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1875–1877
Total synthesis of dehydroaltenusin
Shunya Takahashi,a,* Shinji Kamisuki,b Yoshiyuki Mizushina,c Kengo Sakaguchi,b Fumio Sugawarab
and Tadashi Nakataa
aRIKEN (The Institute of Physical and Chemical Research), Wako-shi, Saitama, 351-0198, Japan
bDepartment of Applied Biological Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan
cLaboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe,
Hyogo 651-2180, Japan
Received 25 December 2002; accepted 8 January 2003
Abstract—First total synthesis of dehydroaltenusin, a natural enzyme inhibitor, is described. The key step involves Suzuki-couplig
reaction of aryl triflate prepared from 2,4,6-trihydroxy benzoic acid with a catechol-derived boronic acid. The synthetic sample
was evaluated as a potent inhibitor against an eukaryotic DNA polymerase a. © 2003 Elsevier Science Ltd. All rights reserved.
Dehydroaltenusin was first discovered from mycelium
extracts of Alternaria tennuis and A. kikuchiana by
Rosett et al. in 1957.1 Since then, this compound has
been found from a variety of fungi.2,3 The structure was
initially suggested to be a g-lactone derivative of b-
resorcylic acid monomethylether based on the chemical
and spectroscopic data2 and later revised to 1 possesing
a d-lactone ring by the X-ray crystallographic analyses
(Fig. 1).4 In 1995, 1 was reported to inhibit the calmod-
ulin-dependent activity of myosin light chain kinase
(MLCK) with IC50 value of 0.69 mM.5 Recently, we
have also isolated (−)-1 from Acremonium sp.
98H02B04-1 (2) and shown it to be a powerful mam-
malian DNA polymerase a inhibitor.6 These results
suggest that 1 might be a promising biological tool.
However its low producibility has prevented such uti-
lization. Furthermore, no total synthesis of 1 or (−)-1
has been reported so far, and the absolute configuration
of (−)-1 has still remained unsolved. In connection with
our studies directed towards total synthesis of (−)-1, we
report herein the first synthesis of 1 and its inhibitory
activity against a couple of DNA polymerases.
Our synthetic efforts toward
1 involved Suzuki-
coupling7 reaction of an aryl triflate 2 with an aryl
boronic acid 3 as a key step. Synthesis of the aryltriflate
2 started from 2,4,6-trihydroxybenzoic acid 4.8 Accord-
ing to Danishefsky’s method,9 the carboxylic acid 4 was
transformed into 1,3-benzodioxin 5 in 43% yield
(Scheme 1). Regioselective methylation of 5 was per-
formed by Mitsunobu conditions10 with diisopropyl
azodicarboxylate-triphenyl phosphine in the presence of
methanol to afford monomethyl ether 611 in 89% yield.
Treatment of 6 with triflic anhydride-pyridine gave the
corresponding triflate 2 in 94% yield. On the other
hand, a 4-bromocatechol 812 prepared from 4-methyl-
8
catechol (7)
was subjected to methoxymethylation
(NaH, MOMCl), giving bis-MOM ether 9 in 90% yield.
Halogen–lithium exchange (n-BuLi, THF, −78 to
−40°C) of 9 followed by trapping with triisoproyl
borate (Et2O, −78°C–rt) afforded an aryl boronic acid 3
in 95% yield. This compound was, without purification,
employed to the next coupling reaction, because of its
instability.
Introduction of a catechol moiety into 2 was best
realized by using 1.5 equiv. of 3 in the presence of
tetrakis(triphenylphospine)palladium (0.05 mol equiv.),
K3PO4 (1.5 equiv.) and KBr (1.0 equiv.) in dioxane13 at
100°C to produce a coupled product 10 in 93% yield.14
Alkaline hydrolysis of 10 and subsequent acid treat-
ment provided artenusin 11 in 64% yield. This com-
Figure 1.
* Corresponding author. Fax: +81-48-462-4666; e-mail: shunyat@
riken.go.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00072-8

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S. Takahashi et al. / Tetrahedron Letters 44 (2003) 1875–1877
Scheme 1. Reagents and conditions: (a) DIAD (1.05 equiv.), Ph3P (1.05 equiv.), MeOH (1.05 equiv.), THF, rt; (b) Tf2O (1.1
equiv.), pyridine, 0°C; (c) MOMCl (2.5 equiv.), NaH (2.5 equiv.), DMF, 0°C; (d) n-BuLi (1.1 equiv.), THF, −78 to −40°C, then
(i-PrO)3B (1.1 equiv.), Et2O, −78°C–rt; (e) (Ph3P)4Pd (0.05 equiv.), K3PO4 (1.50 equiv.), KBr (1.0 equiv.), dioxane, 100°C; (f) 2N
KOH, EtOH, 60°C; (g) 10% HCl–MeOH, CH2Cl2, rt; (h) BCl3 (10 equiv.), CH2Cl2, 0°C–rt; (i) FeCl3, aq. EtOH, rt.
pound was also obtained by the action of BCl3 in
CH2Cl2 from 10 in a single step (60%). Finally, FeCl3-
promoted oxidation1 of 11 afforded dehydroaltenusin
(1)15 in 82% yield. The spectral and physical properties
of 1 were identical with those of natural 1.
examined and compared with those of natural (−)-1. As
illustrated in Figure 2, the IC50 values of 1 and (−)-1 for
DNA polymerase a were 0.8 and 0.7 mM, respectively.
Therefore, the inhibitory activity of the two compounds
was not distinguishable.
In summary, the first synthesis of dehydroaltenusin (1)
has been accomplished in 7 steps with an 18% overall
yield from a commercially available carboxylic acid 4.
This synthetic process would be quite useful for prepa-
ration of many analogs of 1 suitable for clinical usage.
Now asymmetric synthesis of (−)-1 and determination
of the absolute configuration are underway.
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Figure 2. Inhibition of eukaryotic DNA polymerase a and b.
The synthetic 1 and natural (−)-1 are depicted as open and
closed symbols, respectively. Inhibition activity against DNA
polymerase a and b are shown as square and circle symbols,
respectively. DNA polymerase activity in the absence of com-
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DNA polymerase inhibition assay was performed as
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(0.05 units) and rat DNA polymerase b (0.05 units)
inhibitory activity of the synthetic compound 1 were

S. Takahashi et al. / Tetrahedron Letters 44 (2003) 1875–1877
1877
8. Both compounds are commercially available.
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d, J=2.4 Hz), 6.69 (1H, s), 6.73 (1H, d, J=2.4 Hz), 11.29
(1H, s); 13C NMR (100 MHz, CDCl3) l 29.6, 56.0, 79.1,
99.8, 103.6, 104.3, 116.1, 120.7, 134.9, 145.9., 152.9,
164.5, 166.2, 167.2, 180.6; HRMS (FAB) calcd for
C15H11O6 (M-H)− 287.0556, found 287.0563.
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15. Mp 189–190°C; 1H NMR (400 MHz, CDCl3) l 1.73
(3H, s), 3.91 (3H, s), 6.28 (1H, s), 6.41 (1H, s), 6.63 (1H,