Efficient synthesis of biologically active (±)-confluentin and (±)-daurichromenic acid

Article abstract of DOI:10.1080/00397910600941224

One-step synthesis of biologically active (±)-confluentin is described from commercially available orcinol with trans,trans-farnesal in the presence of ethylenediamine diacetate as a catalyst. Further conversion of synthetic confluentin to highly potent anti-HIV agent, (±)-daurichromenic acid, is accomplished by formylation and oxidation in two steps. Copyright Taylor & Francis Group, LLC.

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Efficient Synthesis of Biologically Active
(±)‐Confluentin and (±)‐Daurichromenic Acid
Yong Rok Lee a , Xue Wang a , Seok Kyun Noh a & Won Seok Lyoo b
a School of Chemical Engineering and Technology, Yeungnam University ,
Gyeongsan, Korea
b School of Textiles, Yeungnam University , Gyeongsan, Korea
Published online: 23 Nov 2006.
To cite this article: Yong Rok Lee , Xue Wang , Seok Kyun Noh & Won Seok Lyoo (2006) Efficient Synthesis
of Biologically Active (±)‐Confluentin and (±)‐Daurichromenic Acid, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:22, 3329-3334, DOI:
10.1080/00397910600941224
To link to this article: http://dx.doi.org/10.1080/00397910600941224
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Synthetic Communicationsw, 36: 3329–3334, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600941224
Efficient Synthesis of Biologically
Active (+)-Confluentin
and (+)-Daurichromenic Acid
Yong Rok Lee, Xue Wang, and Seok Kyun Noh
School of Chemical Engineering and Technology, Yeungnam University,
Gyeongsan, Korea
Won Seok Lyoo
School of Textiles, Yeungnam University, Gyeongsan, Korea
Abstract: One-step synthesis of biologically active (+)-confluentin is described from
commercially available orcinol with trans,trans-farnesal in the presence of ethylene-
diamine diacetate as a catalyst. Further conversion of synthetic confluentin to highly
potent anti-HIV agent, (+)-daurichromenic acid, is accomplished by formylation
and oxidation in two steps.
Keywords: Confluentin, anti-HIV agent, daurichromenic acid
Confluentin (1) and its derivatives, daurichromene A (2) and B (3), were
recently isolated from Rhododendron dauricum, a plant found in areas of
northern China, eastern Siberia, Mongolia, Hokkaido, and Japan (Fig. 1).[1]
The dried leaves of this plant are known as “Manshanfong” in China and are
used in medicines as an expectorant and treatment for acute chronic bronchi-
tis.[2] Confluentin (1) and its derivatives have shown to have an inhibitory
effect on histamine release.[1] Daurichromenic acid (4), rhododaurichromanic
acid A (5), and rhododaurichromanic acid B (6) were also isolated from the
same plant. Daurichromenic acid (4) has shown highly potent anti-HIV
activity in acutely infected H9 cells with an EC50 of 0.00567 mg/mL and a
Received in Japan January 20, 2006
Address correspondence to Yong Rok Lee, School of Chemical Engineering and
Technology, Yeungnam University, Gyeongsan 712-749, Korea. E-mail: yrlee@yu.
ac.kr
3329

3330
Y. R. Lee et al.
Figure 1. Biologically active natural products isolated from Rhododendron dauricum.
therapeutic index (TI) of 3710.[3] Rhododaurichromanic acid A (5) has also
shown potent anti-HIV activity with an EC50 value of 0.37 mg/mL and a TI
of 91.9.[3] Interestingly, natural confluentin and daurichromenic acid derivatives
have been isolated from same sources, but their absolute configurations of C-2
are different from each other. The absolute configuration of confluentin (1) was
known as R from its circular dichroism spectrum.[1] The absolute stereo-
chemistry of daurichromenic acid (4) was confirmed as S from X-ray crystallo-
graphic analysis and photochemical conversion by Kashiwada.[3a] These
attractive biological activities have stimulated interest in the synthesis of
naturally occurring confluentin (1) and daurichromenic acid (4). We describe
here concise synthesis of (+)-confluentin (1) and (+)-daurichromenic acid (4).
The synthesis of confluentin (1) is carried out as shown in Scheme 1. The
synthesis of the benzopyran skeleton as a core was first examined from com-
mercially available orcinol (7) under several conditions.The methods for the
preparation of 2H-benzopyrans have been reported by many groups.[4]
Among these, the reaction conditions using Ca(OH)2/EtOH or
pyridine/1408C developed by Shigemasa[4c] or Zamarlik[4f] appeared to be
quite promising for the synthesis of benzopyrans. However, in these reaction
conditions, no expected benzopyrans were produced.It has been reported by
Scheme 1.

(+)-Confluentin and (+)-Daurichromenic Acid
3331
Tietze that ethylenediamine diacetate–catalyzed reactions of 1,3-dicarbonyl
compounds with enals readily afforded 2H-pyrans.[5] We investigated the
possibility of the use of this reagent for the synthesis of confluentin (1) with
the benzopyran skeleton. Surprisingly, reaction of 7 with trans,trans-farnesal
(8) in the presence of 10 mol% of ethylenediamine diacetate in refluxing
xylene for 5 h gave adduct 1 in 65% yield. The spectroscopic data of our
synthetic material 1 are in agreement with those reported in the literature.[6]
Recently, the total syntheses of daurichromenic acid (4), rhododaurichro-
manic acid A (5), and rhododaurichromanic acid B (6) have been reported by
three groups.[7–9] Hsung and coworkers reported the total synthesis of the
methyl ester of 4 starting from 5-methyl-1,3-cyclohexanedione in three steps
(22%, overall yields).[7] The subsequent photochemical reaction and the
hydrolysis of the methyl ester of 4 afforded rhododaurichromanic acid A (5)
and rhododaurichromanic acid B (6) as a mixture. Another synthetic
approach of 4 was accomplished by Jin and coworkers staring from orcinol
in five steps (49%, overall yields).[8] More recently, another concise
synthesis of 4 has been reported by Wilson and coworkers from ethyl acetoa-
cetate in four steps (6%, overall yields).[9] Although there are currently several
methods available to synthesize daurichromenic acid (4), rhododaurichroma-
nic acid A (5), and rhododaurichromanic acid B (6), general and more
efficient synthetic routes are still desired. Our concise synthetic route to daur-
ichromenic acid (4) is shown in Scheme 2. We have used synthetic material 1 as
a starting material to complete the total synthesis of 4.We found that formyla-
tion of 1 using POCl3/DMF with the well-known Vilsmeier–Haack reaction
gave only 10% yield of the desired product 9.[10] The yield was improved to
40% when 1 was treated with oxalyl chloride/DMF in acetonitrile at 08C. Sub-
sequent oxidation of 9 with buffered sodium chlorite at room temperature for
10 h led to 4 in 78% yield.[11] The spectroscopic data of the synthetic
material 4 are in full agreement with those reported in the literature.[3a]
Scheme 2.

3332
Y. R. Lee et al.
In conclusion, a one-step synthesis of confluentin (1) has been accom-
plished from commercially available orcinol (7) in 65% yield. Conversion
of 1 to biologically active daurichromenic acid (4) is also carried out with
the modified Vilsmeier–Haack reaction and oxidation. Further synthetic
approaches of the analogues of 4 are in progress to screen structure–
activity relationships of this potent anti-HIV lead compound.
EXPERIMENTAL
All experiments were carried out under a nitrogen atmosphere. Merck
precoated silica-gel plates (Art. 5554) with fluorescent indicator were used
for analytical thin-layer chromatography (TLC). Flash column chromato-
1
graphy was performed using silica gel 9385 (Merck). H NMR spectra were
recorded on a Bruker model ARX(300-MHz) spectrometer. 13C NMR
spectra were recorded on a Bruker model ARX(75-MHz) spectrometer in
CDCl3 using d ¼ 77.5 ppm as the solvent chemical shift. IR spectra were
recorded on a Jasco 5300 (Jasco FTIR 5300) spectrophotometer. High resol-
ution mass (HRMS) spectra were carried out by Korea Basic Science Institute.
Confluentin (1)
Orcinol (7) (248 mg, 2 mmol) and trans,trans-farnesal (528 mg, 2.4 mmol)
were dissolved in xylene (20 mL), and ethylenediamine diacetate (36 mg,
0.2 mmol) was added at room temperature. The mixture was refluxed for
5 h and then cooled to room temperature. Removal of solvent at reduced
pressure left an oily residue, which was then purified by column chromato-
graphy on silica gel using hexane/ethyl acetate (20:1) to give product 1
1
(424 mg, 65%) as a yellow oil: H NMR (300 MHz, CDCl3) d 1.35 (s, 3H),
1.55 (s, 3H), 1.56 (s, 3H), 1.65 (s, 3H), 1.65–1.77 (m, 2H), 1.87–2.12
(m, 6H), 2.16 (s, 3H), 4.74 (s, 1H), 5.03–5.11 (m, 2H), 5.48 (d, 1H, J ¼
9.9 Hz), 6.09 (s, 1H), 6.22 (s, 1H), 6.59 (d, 1H, J ¼ 9.9 Hz); 13C NMR
(75 MHz, CDCl3) d 16.4, 18.1, 21.9, 23.1, 26.2, 26.7, 27.1, 40.1, 41.4, 78.7,
107.4, 109.0, 109.9, 117.5, 124.5, 124.8, 127.3, 131.7, 135.6, 139.9, 151.9,
154.4; IR (neat) 3429, 2969, 2922, 1626, 1580, 1451, 1377, 1144, 1076,
991 cm21; HRMS m/z (Mþ) calcd. for C22H30O2: 326.2246. Found:
326.2248.
5-Hydroxy-2,7-dimethyl-2-(4,8-dimethyl-3E,7-nonadienyl)-2H-
chromene-6-carbaldehyde (9)
To a solution of DMF (395 mg, 5.0 mmol) in acetonitrile (5 mL), oxalyl
chloride (571 mg, 4.5 mmol) was added under nitrogen and stirred for

(+)-Confluentin and (+)-Daurichromenic Acid
3333
30 min at 08C. A solution of 1 (164 mg, 0.5 mmol) in acetonitrile (1 mL) was
then added dropwise at 08C. After stirring overnight at room temperature, the
reaction mixture was hydrolyzed with 10% NaOH solution (20 mL) and the
aqueous layer extracted with ethyl acetate (3 ꢀ 20 mL). The combined
organic layer was washed with water and dried over anhydrous MgSO4.
Removal of solvent at reduced pressure left an oily residue, which was then
purified by column chromatography on silica gel using hexane/ethyl acetate
1
(15:1) to give product 9 (71 mg, 40%) as a yellow oil: H NMR (300 MHz,
CDCl3) d 1.38 (s, 3H), 1.54 (s, 3H), 1.56 (s, 3H), 1.64 (s, 3H), 1.60–1.82
(m, 2H), 1.85–2.11 (m, 6H), 2.44 (s, 3H), 5.03–5.10 (m, 2H), 5.46 (d, 1H,
J ¼ 10.1 Hz), 6.13 (s, 1H), 6.67 (d, 1H, J ¼ 10.1 Hz), 9.99 (s, 1H), 12.64
(s, 1H); 13C NMR (75 MHz, CDCl3) d 16.4, 18.1, 18.7, 23.0, 26.1, 27.0,
27.7, 39.9, 42.1, 81.0, 107.3, 111.4, 113.5, 116.2, 124.0, 124.7, 126.7,
131.7, 135.9, 144.0, 161.0, 161.5, 193.2; IR (neat) 2967, 2926, 1640, 1568,
1483, 1451, 1385, 1294, 1252, 1157, 1063, 1003, 897 cm21; HRMS m/z
(Mþ) calcd. for C23H30O3: 354.2195. Found: 354.2196.
(+)-Daurichromenic Acid (4)
To a solution of the aldehyde 9 (100 mg, 0.28 mmol) in t-butanol (3 mL),
acetonitrile (3 mL), 2-methyl-2-butene (2 mL), and 1,2-dimethoyethane
(DME) (1 mL), NaH2PO4 (168 mg, 1.40 mmol) and NaClO2 (127 mg,
1.40 mmol, dissolved in 1 mL of water) were added at 08C. The resulting
mixture was warmed slowly to room temperature and stirred for 12 h. Brine
(15 mL) was added, and the resultant solution was extracted with ethyl
acetate (20 mL ꢀ 3). The combined organic extracts were washed with
brine (10 mL), dried over anhydrous MgSO4, and concentrated in vacuum.
The crude product was then purified by flash chromatography using
1
hexane/ethylacetate (1:1) as the eluant to afford 4 (163 mg, 78%): H NMR
(300 MHz, CDCl3) d 1.38 (s, 3H), 1.55 (s, 3H), 1.57 (3H, s), 1.65 (s, 3H),
1.70–1.80 (m, 2H), 1.86–2.12 (m, 6H), 2.51 (s, 3H), 5.03–5.10 (m, 2H),
5.46 (d, 1H, J ¼ 10.1 Hz), 6.23 (s, 1H), 6.71 (d, 1H, J ¼ 10.1 Hz), 11.72
(s, 1H); 13C NMR (75 MHz, CDCl3) d 16.1, 17.7, 22.6, 24.6, 25.7, 26.8,
27.2, 39.7, 41.7, 80.3, 103.6, 107.0, 112.3, 116.7, 129.9, 124.4, 126.5,
131.4, 135.6, 144.5, 159.1, 160.7, 176.3; IR (neat) 2926, 1620, 1454, 1381,
1269, 1177, 908 cm21; HRMS m/z (Mþ) calcd. for C23H30O4: 370.2144.
Found: 370.2142.
ACKNOWLEDGMENT
This work was supported by grant No. RTI04-01-04 from the Regional
Technology Innovation Program of the Ministry of Commerce, Industry,
and Energy (MOCIE).

3334
Y. R. Lee et al.
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