First total synthesis of desmosdumotin C

Article abstract of DOI:10.1081/SCC-200063907

Desmosdumotin C (1), a novel compound isolated from the roots of Desmos dumosus, was synthesized from 2,4,6-trihydroxyacetophenone (2), confirming the assigned structure of the natural product. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200063907

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First Total Synthesis of
Desmosdumotin C
Kyoko Nakagawa‐Goto a , Jiu‐Hong Wu b &
Kuo‐Hsiung Lee a
a Natural Products Laboratory, School of Pharmacy ,
University of North Carolina , Chapel Hill, North
Carolina, USA
b Department of Pharmacy , Beijing, China
Published online: 15 Aug 2006.
To cite this article: Kyoko Nakagawa‐Goto , Jiu‐Hong Wu & Kuo‐Hsiung Lee
(2005) First Total Synthesis of Desmosdumotin C , Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:13,
1735-1739, DOI: 10.1081/SCC-200063907
To link to this article: http://dx.doi.org/10.1081/SCC-200063907
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Synthetic Communicationsw, 35: 1735–1739, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200063907
First Total Synthesis of Desmosdumotin C†
Kyoko Nakagawa-Goto
Natural Products Laboratory, School of Pharmacy, University of North
Carolina, Chapel Hill, North Carolina, USA
Jiu-Hong Wu
Department of Pharmacy, Beijing, China
Kuo-Hsiung Lee
Natural Products Laboratory, School of Pharmacy, University of North
Carolina, Chapel Hill, North Carolina, USA
Abstract: Desmosdumotin C (1), a novel compound isolated from the roots of Desmos
dumosus, was synthesized from 2,4,6-trihydroxyacetophenone (2), confirming the
assigned structure of the natural product.
Keywords: Antitumor, cytotoxicity, desmosdumotin C, total synthesis
INTRODUCTION
Desmosdumotin C, a novel compound,[1] was isolated recently by our group
from the roots of Desmos dumosus. The structure of 1, which was established
mainly by NMR and X-ray analyses, has a cyclohexe-4-ene-1,3-dione
skeleton with a conjugated cinnamoyl moiety on the C-2 position and a
gem-dimethyl group on the C-6 position. Similar compounds, safflomin
C,[2] syzygiol,[3] and uliginosin A analog,[4] are known. Although these
latter compounds exist as tautomeric mixtures, the isolated desmosdumotin
C exists as one enolic tautomer.
Received in the USA June 27, 2004
†Antitumor agent 242
Address correspondence to Kuo-Hsiung Lee, Natural Products Laboratory, School
of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360, USA.
Tel.: 919-962-0066; Fax: 919-966-3893; E-mail: khlee@unc.edu
1735

1736
K. Nakagawa-Goto, J.-H. Wu, and K.-H. Lee
Figure 1. The structure of Desmosdumotin C.
Desmosdumotin C (1) represents a promising new anticancer lead
structure for further new analog development based on its in vitro evaluation
against a panel of six cancer cell lines.[1] Thus, to obtain a larger quantity than
available from the plant source and to confirm the structure of the natural
product, we herein report the first simple total synthesis of 1.
EXPERIMENTAL
Reaction of 2,4,6-trihydroxyacetophenone (2) with three equivalents of
methyl iodide in the presence of sodium methoxide produced 2-acetyl-3-
hydroxy-4,6,6-trimethylcyclohexa-2,4-dienone (3)[5] in 56% yield along
with tetramethyl 4 in 9% yield. The selective methoxylation of 3 to give 5
was achieved in 88% yield by treatment with TMSCHN2 at a low temperature.
Employing a higher temperature gave a low yield of the desired compound,
because of the production of unknown side product(s). The use of other con-
ditions, such as K2CO3 and MeI or Li2CO3 and MeI,[6] yielded only tetra-
methyl derivative 4, because of the presence of a strongly acidic proton on
the C-4 position (Scheme 1).
Scheme 1. Reagents and conditions: a) MeI (3.3 mol eq.), 30% NaOMe in MeOH
(3.7 mol eq.), MeOH, reflux, 7 h; b) 2.0 M TMSCHN2 in Et2O (excess), EtOAc/
MeOH, 278 8C, 3 h; c) 50% KOH aq., EtOH, PhCHO, rt, 23 h.

Synthesis of Desmosdumotin C
1737
Finally, desmosdumotin C (1) was obtained in 78% yield by the aldol con-
densation of 5 with benzaldehyde in 50% KOH aqueous solution. Recrystalli-
zation from CHCl3–MeOH gave 1 as yellow needles. The synthetic product
has identical spectral data with those of the natural product.
All melting points were taken on Fisher-Johns and Mel-Temp II melting-
point instruments and are uncorrected. IR spectra were recorded on a Perkin-
Elmer 1320 spectrophotometer. 1H NMR spectra were obtained using a Varian
Gemini 2000 (300-MHz) NMR spectrometer with TMS as the internal
standard. All chemical shifts are reported in ppm. FABMS and HRFABMS
spectral analyses were determined on a JOEL HX-110 instrument. Analytical
thin-layer chromatography (TLC) was carried out on Merck precoated
aluminum silica-gel sheets (Kieselgel 60 F-254). All target compounds were
1
characterized by H, IR, and MS analyses.
2-Acetyl-3,5-dihydroxy-4,6,6-trimethylcyclohexa-2,4-dione (3)
A solution of 2,4,5-trihydroxyacetophenone (2, 487 mg, 2.9 mmol) and
sodium methoxide (1.95 mL, 10.8 mmol, 30% MeOH solution) in anhydrous
MeOH (3 mL) containing methyl iodide (0.6 mL, 9.6 mmol) was refluxed
for 7 h. The reaction mixture was cooled to 0 8C and acidified with 1 N of
aqueous HCl, then extracted three times with EtOAc. The combined
organic layers were dried over Na2SO4 and concentrated in vacuo. The
residue was chromatographed on silica gel with EtOAc–hexane (1:9 to
1:4, v/v) as an eluent to provide 3 (343 mg, 56%). Pale yellow prisms, mp:
164–165 8C (EtOAc–hexane). IR (KBr): 3099 (br), 1656, 1590, 1525,
1
1474, 1387, 1331, 1278, 1193, 1153 cm21. H NMR (300 MHz, DMSO-d6):
d ¼ 18.94 (br s, 1H, chelated-OH), 2.42 [s, 3H, C(O)CH3], 1.73 (s, 3H,
CH3), 1.23 (s, 6H, CH3 ꢀ 2). 13C NMR (300 MHz, DMSO-d6): d ¼ 199.4
(C55O), 196.0 (C55O), 188.7 (C–OH), 176.2 (C–OCH3), 105.0 (C-2),
101.7 (C-6), 48.2 [C(CH3)2], 27.8 [C(O)CH3], 24.3 (CH3 ꢀ 2), 7.3 (CH3).
MS m/z 209 (Mþ 2 1).
2-Acetyl-3-hydroxy-5-methoxy-4,6,6-trimethylcyclohexa-2,4-dione (5)
To a solution of 3 (447 mg, 2.13 mmol) in anhydrous EtOAc–MeOH (5:1,
6 mL), a solution of TMSCHN2 in diethyl ether (5 mL, 10 mmol, 2 M) was
added slowly at 278 8C under argon atmosphere, and the mixture was
stirred for 2 h. At this time, a second aliquot of TMSCHN2 (4 mL, 8 mmol,
2 M) was added and stirring was continued at 278 8C. Acetic acid was then
added to destroy the excess TMSCHN2. The mixture was concentrated in
vacuo, and the residue was purified by silica-gel column chromatography
with EtOAc–hexane (1:2) as an eluent to obtain 5 (418 mg, 88%). Yellow
oil: IR (KBr): 2979, 2937, 2874, 1659, 1636, 1536, 1469, 1374, 1202, 1131,

1738
K. Nakagawa-Goto, J.-H. Wu, and K.-H. Lee
978, 915 cm21. 1H NMR (300 MHz, CDCl3): d ¼ 18.93 (s) and 18.14 (s) (2:1,
1H, chelated-OH), 3.93 (s) and 3.85 (s) (2:1, 3H, OCH3), 2.69 (s) and 2.59 (s)
[1:2, 3H, C(O)CH3], 1.95 (s) and 1.90 (s) (2:1, 3H, CH3), 1.43 (s) and 1.31 (s)
(1:2, 6H, CH3 ꢀ 2). 13C NMR (300 MHz, CDCl3) d C–H COSY (gem-
dimethyl), 7.3. MS m/z 223 (Mþ 2 1).
Desmosdumotin C (1)
A solution of 4 (62 mg, 0.28 mmol) in EtOH (1 mL) and 50% KOH in water
(1 mL) containing benzaldehyde (0.1 mL, 0.99 mmol) was stirred at rt for
23 h. The reaction mixture was poured into 1 N of ice-cold HCl, then
extracted with CH2Cl2. The extract was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was chromatographed on
silica gel with EtOAc–hexane (1:9, v/v) as an eluent to afford a crystalline
solid (80 mg). Recrystallizaton from CH2Cl2–MeOH gave desmosdumotin
C (39 mg without its tautomer) as yellow needles (Figure 1). A second recrys-
tallization of the mother liquor using CH2Cl2–hexane gave 29 mg of 1, as a
mixture with its tautomer. In sum, 68 mg (78%) of 1 were obtained. Yellow
needles, mp 98–99 8C (CHCl3–MeOH, lit.: 96–97 8C). IR (KBr): 3101,
2978, 2936, 1656, 1623, 1514, 1448, 1425, 1203, 1152, 1119, 977, 944,
1
759, 698 cm21. H NMR (300 MHz, CDCl3): d ¼ 19.17 (s, 1H, chelated-
OH), 8.33 (d, 1H, J ¼ 15.5 Hz), 7.92 (d, 1H, J ¼ 15.5 Hz), 7.71–7.62
(m, 2H, Ar-200, 600-H), 7.42–7.34 (m, 3H, Ar-300, 400, 500-H), 3.95 (s, 3H,
OCH3), 1.99 (s, 3H, Ar-CH3), 1.37 (s, 6H, CH3 ꢀ 2). 13C-NMR (300 MHz,
CDCl3): d ¼ 198.0 (C-1), 192.4 (C-3), 187.2 (C-10), 176.6 (C-5), 144.9 (C-
20, C-30), 135.2 (C-100), 130.6 (C-300, C-500), 128.8 (C-400), 123.2 (C-200,
C-600), 113.6 (C-2), 106.6 (C-4), 62.1 (OCH3), 50.4 (C-6), 24.3 (CH3 ꢀ 2),
9.8 (Ar-CH3). MS m/z 313 (Mþ þ 1).
ACKNOWLEDGMENTS
This study was supported by NIH Grant CA17625 awarded to K. H. L. Thanks
are also due to Grant No. 30271533 awarded to J. H. W. from the National
Natural Science Foundation of China.
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Synthesis of Desmosdumotin C
1739
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