Stereochemistry of phellinsin A: A concise synthesis of α-arylidene-γ-lactones

Article abstract of DOI:10.1081/SCC-200054845

Phellinsin A (1a) was prepared in a concise way, thereby elucidating the relative stereochemistry of the aryl and carboxylic acid groups in 1a. The synthesis employed selective monohydrolysis of the dilactones derived from oxidative dimerization of cinnamic acid derivatives. This approach provided a practical synthetic route to α-arylidene-γ-lactones. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200054845

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Stereochemistry of Phellinsin
A: A Concise Synthesis of
α‐Arylidene‐γ‐Lactones
Eungsoo Kim a , Hyeong Kyu Lee a , Eui‐Il Hwang a
, Sung‐Uk Kim a , Woo Song Lee a , Sangku Lee a
Sang‐Hun Jung b
&
a Korea Research Institute of Bioscience and
Biotechnology , Yusong, Taejon, Republic of Korea
b College of Pharmacy , Chungnam National
University , Taejon, Republic of Korea
Published online: 16 Aug 2006.
To cite this article: Eungsoo Kim , Hyeong Kyu Lee , Eui‐Il Hwang , Sung‐Uk Kim ,
Woo Song Lee , Sangku Lee & Sang‐Hun Jung (2005) Stereochemistry of Phellinsin
A: A Concise Synthesis of α‐Arylidene‐γ‐Lactones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:9,
1231-1238, DOI: 10.1081/SCC-200054845
To link to this article: http://dx.doi.org/10.1081/SCC-200054845
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Synthetic Communicationsw, 35: 1231–1238, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054845
Stereochemistry of Phellinsin A: A Concise
Synthesis of a-Arylidene-g-Lactones
Eungsoo Kim, Hyeong Kyu Lee, Eui-Il Hwang, Sung-Uk Kim,
Woo Song Lee, and Sangku Lee
Korea Research Institute of Bioscience and Biotechnology, Yusong,
Taejon, Republic of Korea
Sang-Hun Jung
College of Pharmacy, Chungnam National University, Taejon,
Republic of Korea
Abstract: Phellinsin A (1a) was prepared in a concise way, thereby elucidating the
relative stereochemistry of the aryl and carboxylic acid groups in 1a. The synthesis
employed selective monohydrolysis of the dilactones derived from oxidative dimeriza-
tion of cinnamic acid derivatives. This approach provided a practical synthetic route to
a-arylidene-g-lactones.
Keywords: a-Arylidene-g-lactone, cinnamic acid, dilactone, hydrolysis
Phellinsin A (1a), isolated from the cultured broth of Phellinus sp. PL3, is an
inhibitor of chitin synthases II, which renders it a potentially useful antifungal
agent.[1] Structurally, phellinsin A is a phenolic lignan featuring a dehydrodi-
merized g-lactone form of caffeic acid, and it occurs in a racemic form despite
the presence of two asymmetric centers. The connectivity of 1a was estab-
lished by NMR analysis; however, the relative stereochemistry of two neigh-
boring aryl and carboxylic acid moieties in 1a was not elucidated. For the
Received in Japan November 4, 2004
Address correspondence to Sangku Lee, Korea Research Institute of Bioscience and
Biotechnology, 52 Oun,, Yusong, Taejon 305-333, Republic of Korea. Tel.: þ 82-42-
860-4552; Fax: þ82-42-860-4309; E-mail: sangku@kribb.re.kr

1232
E. Kim et al.
development of new potent analogues of 1a, the stereochemistry of 1a needs
to be established. Herein we describe the synthesis of phellinsin A (1a),
thereby establishing the relative stereochemistry of 1a and providing an
efficient synthetic route to a-arylidene-g-lactones,[2] which constitute an
important group in natural products.[3]
Oxidative dimerization of free phenolic cinnamic acids, ferulic acid, and
sinapic acid to the corresponding dilactones using FeCl3 as an one-electron
oxidant was reported in nearly sixty years ago.[4] Recently, Yuzikhin and
coworkers utilized lead dioxide in CF3COOH-CH2Cl2 as an one-electron
oxidant for the oxidative dimerization of cinnamic acid derivatives to the cor-
responding dilactones.[5] They showed that alkoxy-, alkyl-, and halogen-
substituted cinnamic acids provided the corresponding dilactones. It is
known that the oxidative dimerization reaction involves the formation of rela-
tively stable radical cations and the dimerization of the resulting radicals,
followed by intramolecular cyclization to yield the corresponding
dilactone.[5,6]
We have interested in the construction of the ring skeleton of phellinsin
A (1a) via oxidative dimerization of cinnamic acid derivatives 3 to the
corresponding dilactones 2 and monohydrolysis of the resulting dilactones,
followed by dehydration to furnish the a-arylidene-g-lactone moieties 1 as
shown in retrosynthetic analysis (Scheme 1). One-electron oxidation
would be expected to provide thermodynamically more stable cis-ring
fused-dilactones positioning exo-orientation of aryl groups, which upon
mono-hydrolysis of the dilactone would generate the trans-relationship of
the carboxylic acid and aryl moieties in 1. We envisioned that this strategy
could provide a simple way of preparing phellinsin A (1a), thereby establish-
ing the relative stereochemistry of 1a and providing an efficient synthetic route
to a-arylidene-g-lactones 1.
Dehydrodiferulic dilactone (2b) was obtained in 56% yield from ferulic
acid (3b) by slight modification of Haworth’s method.[4] The stage was set
for the mono-hydrolysis of the dilactone 2b, followed by dehydration to
Scheme 1.

Stereochemistry of Phellinsin A
1233
produce a-arylidene-g-lactone 1b (Scheme 2). To this end, dilactone 2b was
treated with 1 NaOH at room temperature for 5 min to furnish g-lactone 1b in
86% yield. For the preparation of phellinsin A (1a), compound 1b was
demethylated by treatment with BBr3 in methylene chloride at 08C to afford
1a. The E-configuration of the double bond in 1a was established by
NOESY and COSY experiments. We observed NOE effects between Hb
and Hc. The trans-orientation of the aryl and carboxylic acid groups in 1a
was confirmed by a small coupling constant (Ja,b ¼ 2.0–2.4 Hz) and a com-
parison to literature data of the methyl esters of 1b[7] and 1f.[8] The
synthetic compound 1a was in good accord with a natural authentic sample
1
in all aspects including IR, H-NMR, 13C-NMR, and TLC in three different
solvent systems. Accordingly, the relative stereochemistry of the aryl
and carboxylic acid groups in phellinsin A (1a) was determined to be trans-
relation. This approach, a sequence of oxidative dimerization of substituted
cinnamic acid to the corresponding dilactone and subsequent monohydro-
lysis of the dilactone, provided a practical way to synthesize phellinsin A (1a).
Having clarified the synthesis of phellinsin A (1a) via monohydrolysis of
the corresponding dilactone, we demonstrated the synthetic approach to
a-arylidene-g-lactones 1 by preparing analogues of phellinsin A. To this
end, a series of dilactones 2 were prepared from cinnamic acid derivatives 3
using FeCl3 or PbO2 as an oxidant (Table 1).[9] FeCl3 was effective for the
oxidative dimerization of para-hydroxy-substituted cinnamic acids,[4]
whereas PbO2 was used for nonphenolic cinnamic acid derivatives.[5]
Treatment of the dilactones 2 in THF with 1N NaOH at room temperature
for 5 min underwent monohydrolysis of the dilactones, followed by dehy-
dration, to furnish the corresponding a-arylidene-g-lactones 1 in moderate
to good isolated yields.[10] The synthesis of a-arylidene-g-lactones was
completed in two steps starting from cinnamic acid derivatives.
In summary, we have prepared phellinsin A (1a) and its analogs in a
concise way, thereby elucidating the trans-relation of the aryl and carboxylic
acid groups in 1a. The synthesis features monohydrolysis of the dilactones
derived from oxidative dimerization of cinnamic acid derivatives and
followed by dehydration to yield a-arylidene-g-lactones.
Scheme 2.

1234
E. Kim et al.
Table 1. Hydrolysis of dilactones 2 to the corresponding a-arylidene-g-lactones 1
Entry
3
R1
R2
OH
R3
Oxidant
2 (%)a
1 (%)a
1
2
3
4
5
6
7
3b
3c
3d
3e
3f
H
H
H
H
OCH3
H
FeCl3
FeCl3
PbO2
PbO2
FeCl3
2b (56)
2c (52)
2d (42)
2e (36)
2f (75)
2g (90)b
2h (84)c
1b (86)
1c (75)
1d (78)
1e (62)
1f (62)
1g (80)
1h (74)
OH
OC2H5
H
OH
H
H
OCH3
H
OCH3
OCH3
OCH3
OCH3
3g
3h
OCH3
OCH3
aIsolated yield, not optimized.
bPrepared by treatment of 2b with diazomethane.
cPrepared by treatment of 2f with diazomethane.
EXPERIMENTAL
All reactions were conducted under a nitrogen atmosphere using oven-dried
glassware unless otherwise noted. Analytical TLC was done on 0.25 mm
E. Merck precoated silica-gel 60 F254 plates. Visualization was accomplished
with UV light at 254 nm and with phosphomolybdic acid or anisaldehyde
stain. Flash chromatography was performed on silica gel 60 (E. Merck
1
9385, 230–400 mesh). H and 13C NMR spectra were recorded on a Varian
Unity 300 or Varian Inova 400 spectrometer at ambient temperature.
Chemical shifts are reported in ppm relative to tetramethylsilane/CHCl3.
General Procedure for Oxidative Dimerization of 4-Hydroxy-
substituted Cinnamic Acids using FeCl3
To a solution of ferric chloride (9.2 g, 56.7 mmol) in ethanol (100 mL) was
a solution of 4-hydroxy-3-methoxycinnamic acid (3b, 5.0 g,
added
25.7 mmol) in ethanol (30 mL) at room temperature. The reaction mixture
was stirred for 1 h and concentrated in vacuo. The residue was diluted with
water, extracted with ethyl acetate, washed with brine, dried over MgSO4,
and concentrated in vacuo. The resulting residue was chromatographed on
silica gel (1:1 hexane–EtOAc) to afford 5.6 g (56%) of 2b as a white solid.

Stereochemistry of Phellinsin A
1235
2b: Mp 206–2088C (lit.[4b] mp 207–2118C); 1H NMR (300 MHz, acetone-d6)
d 7.86 (s, 2H), 7.06 (d, J ¼ 1.8 Hz, 2H), 6.92 (dd, J ¼ 7.8, 1.8 Hz, 2H), 6.86
(d, J ¼ 7.8 Hz, 2H), 5.78 (brs, 2H), 4.09 (brs, 2H), 3.87 (s, 6H); 13C NMR
(75 MHz, acetone-d6) d 176.1, 148.9, 148.4, 131.0, 119.7, 116.2, 110.5,
83.3, 56.5, 49.2; HRMS (FAB) m/z 387.1092 [(M þ H)þ, calcd. for
C20H19O8 387.1080].
2c: Compound 2c was prepared in 52% yield as a yellow solid from 3c
according to the general procedure. 2c: mp 185–1888C; 1H NMR (300 MHz,
CD3OD) d 7.23 (dd, J ¼ 6.6, 1.8 Hz, 4H), 6.82 (dd, J ¼ 6.6, 1.8 Hz, 4H), 5.75
(s, 2H), 3.93 (s, 2H); 13C NMR (75 MHz, CD3OD) d 177.3, 159.5, 130.6,
128.3, 116.8, 84.1, 49.7; HRMS (FAB) m/z 327.0851 [(M þ H)þ, calcd. for
C18H15O6 327.0869].
2f: Compound 2f was prepared in 75% yield as a pale brown solid from 3f
according to the general procedure. 2f: mp 230–2348C (lit.[4b] mp 227–
1
2358C); H NMR (300 MHz, acetone-d6) d 7.47 (s, 2H), 6.75 (s, 4H), 5.76
(brs, 2H), 4.12 (brs, 2H), 3.84 (s, 12H); 13C NMR (75 MHz, acetone-d6) d
176.7, 149.7, 138.2, 130.5, 105.0, 84.1, 57.4, 49.8; HRMS (FAB) m/z
447.1288 [(M þ H)þ, calcd. for C22H23O10 447.1291].
General Procedure for Oxidative Dimerization of Nonphenolic
Cinnamic Acids using PbO2
To a solution of trifluoroacetic acid (3 mL) in methylene chloride (18 mL) was
added 4-ethoxycinnamic acid (3d, 1.0 g, 5.2 mmol) at 08C. Then, PbO2
(1.24 g, 5.2 mmol) was added and the reaction mixture was sirred for 1 h.
The mixture was poured into ethyl acetate (100 mL), and the organic layer
was washed in succession with water, saturated NaHCO3 and brine, dried
over MgSO4, and concentrated in vacuo. The resulting residue was purified
by flash chromatography on silica gel (4 : 1 hexane–EtOAc) to afford 0.84 g
(42%) of 2d as a white solid.
2d: Mp 163–1648C; 1H NMR (300 MHz, CDCl3) d 7.21 (d, J ¼ 8.7 Hz, 4H),
6.90 (dd, J ¼ 6.6, 1.8 Hz, 4H), 5.88 (s, 2H), 4.02 (q, J ¼ 6.9 Hz, 4H), 3.56
(s, 2H), 1.41 (t, J ¼ 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 174.9,
159.6, 129.8, 126.2, 115.1, 81.9, 63.7, 48.3, 14.7; HRMS (FAB) m/z
383.1485 [(M þ H)þ, calcd. for C22H23O6 383.1495].
2e: Compound 2e was prepared in 36% yield as a pale brown solid from 3e
according to the general procedure. 2e: mp 161–1638C; 1H NMR
(300 MHz, CDCl3) d 7.44–7.30 (m, 10H), 5.93 (s, 2H), 3.56 (s, 2H);

1236
E. Kim et al.
13C NMR (75 MHz, CDCl3) d 174.8, 138.0, 129.2, 129.1, 124.5, 81.7, 48.2;
HRMS (FAB) m/z 295.0982 [(M þ H)þ, calcd. for C18H15O4 295.0970].
General Procedure for Methylation of Hydroxy-substituted
Dilactones
To a solution of dehydrodiferulic dilactone (2b, 0.3 g, 0.77 mmol) in acetone
(20 mL) was added excess of diazomethane in ethyl ether at room temperature.
The reaction mixture was stirred overnight and concentrated in vacuo. The
residue was recrystallized from methanol to yield 0.27 g (90%) of 2g as a
white solid.
2g: Mp 200–2038C; 1H NMR (300 MHz, CDCl3) d 7.03–7.00 (m, 6H), 5.80
(s, 2H), 4.22 (s, 2H), 3.79 (s, 6H), 3.77 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 175.3, 149.4, 149.0, 130.5, 118.8, 111.7, 109.9, 81.7, 55.7, 55.6, 48.1;
HRMS (FAB) m/z 415.1394 [(M þ H)þ, calcd. for C22H23O8 415.1393].
2h: Compound 2h was prepared in 84% yield as a white solid from 2f
according to the general procedure. 2h: mp 200–2028C; 1H NMR
(300 MHz, DMSO-d6) d 6.73 (s, 4H), 5.79 (s, 2H), 4.26 (s, 2H), 3.81
(s, 12H), 3.66 (s, 6H); 13C NMR (75 MHz, DMSO-d6) d 175.3, 153.2,
137.8, 133.9, 103.5, 81.6, 60.0, 56.1, 47.8; HRMS (FAB) m/z 475.1601
[(M þ H)þ, calcd. for C24H27O10 475.1604].
General Procedure for Hydrolysis of Dilactones to the
Corresponding a-Arylidene-g-lactones
To a solution of dehydrodiferulic dilactone (2b, 1.40 g, 3.63 mmol) in THF
(10 mL) was added 1N NaOH (100 mL) at room temperature. The reaction
mixture was stirred for 5 min, acidified with 2N HCl to pH 4, extracted with
ethyl acetate, dried over MgSO4, and concentrated in vacuo. The resulting
residue was purified by flash chromatography on silica gel (9:1 CH2Cl2–
CH3OH) to afford 1.2 g (86%) of 1b as a yellow solid.
1b: Mp 116–1198C; 1H NMR (400 MHz, CD3OD) d 7.55 (s, 1H), 7.36 (s, 1H),
7.15 (d, J ¼ 8.0 Hz, 1H), 6.86 (s, 1H), 6.81 (d, J ¼ 8.0 Hz, 1H), 6.75 (bs, 2H),
5.69 (d, J ¼ 2.0 Hz, 1H), 3.98 (bs, 1H), 3.87 (s, 3H), 3.78 (s, 3H); 13C NMR
(100 MHz, CD3OD) d 178.8, 175.2, 150.4, 149.2, 149.1, 148.0, 140.2, 133.5,
127.5, 126.8, 123.1, 119.3, 116.5, 116.4, 114.6, 110.3, 84.4, 58.1, 56.7, 56.4;
HRMS (FAB) m/z 387.1082 [(M þ H)þ, calcd. for C20H19O8 387.1080].

Stereochemistry of Phellinsin A
1237
1c: Compound 1c was prepared in 75% yield as a white solid from 2c
1
according to the general procedure. 1c: mp decomp.; H NMR (300 MHz,
CD3OD) d 7.57 (s, 1H), 7.56 (d, J ¼ 8.7 Hz, 2H), 7.12 (d, J ¼ 9.0 Hz, 2H),
6.81 (d, J ¼ 9.0 Hz, 2H), 6.76 (d, J ¼ 8.7 Hz, 2H), 5.68 (d, J ¼ 2.4 Hz, 1H),
4.00 (s, 1H); 13C NMR (75 MHz, CD3OD) d 178.1, 174.9, 161.2, 159.0,
140.2, 134.0, 132.6, 128.0, 126.8, 122.2. 116.8, 116.6, 84.0, 57.1; HRMS
(FAB) m/z 327.0857 [(M þ H)þ, calcd. for C18H15O6 327.0869].
1d: Compound 1d was prepared in 78% yield as a brown solid from 2d
according to the general procedure. 1d: mp 100–1028C; 1H NMR
(300 MHz, DMSO-d6) d 7.85 (d, J ¼ 8.7 Hz, 2H), 7.39 (s, 1H), 7.10
(d, J ¼ 8.7 Hz, 2H), 6.92 (d, J ¼ 8.7 Hz, 2H), 6.87 (d, J ¼ 8.7 Hz, 2H), 5.76
(s, 1H), 4.04 (q, J ¼ 7.2 Hz, 2H), 3.96 (q, J ¼ 6.6 Hz, 2H), 3.65 (s, 1H),
1.31 (t, J ¼ 7.2 Hz, 3H), 1.28 (t, J ¼ 6.6 Hz, 3H); 13C NMR (75 MHz,
DMSO-d6) d 172.3, 159.7, 158.2, 133.3, 132.4, 126.9, 126.5, 114.6, 114.5,
63.2, 63.0, 14.6, 14.5; HRMS (FAB) m/z 383.1490 [(M þ H)þ, calcd. for
C22H23O6 383.1495].
1e: Compound 1e was prepared in 62% yield as a white solid from 2e
according to the general procedure. 1e: mp 144–1468C; 1H NMR
(300 MHz, CDCl3) d 7.83 (s, 1H), 7.50–7.28 (m, 10H), 5.81 (s, 1H), 4.25
(s, 1H); 13C NMR (75 MHz, CD3OD) d 177.1, 174.6, 142.3, 139.4, 135.6,
131.7, 131.1, 129.9, 129.8, 129.4, 127.0, 126.3, 84.5, 58.7; HRMS (FAB)
m/z 295.0974 [(M þ H)þ, calcd. for C18H15O4 295.0970].
1f: Compound 1f was prepared in 62% yield as a yellow solid from 2f
1
according to the general procedure. 1f: mp decomp.; H NMR (300 MHz,
CDCl3) d 7.69 (d, J ¼ 1.8 Hz, 1H), 6.77 (s, 2H), 6.51 (s, 2H), 5.69
(d, J ¼ 2.4 Hz, 1H), 4.12 (m, 1H), 3.85 (s, 6H), 3.84 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 174.5, 171.4, 147.4, 147.2, 141.9, 137.7, 135.2, 130.2,
124.4, 118.1, 107.7, 101.9, 80.5, 56.4, 56.3, 53.5; HRMS (FAB) m/z
447.1286 [(M þ H)þ, calcd. for C22H23O10 447.1291].
1g: Compound 1g was prepared in 80% yield as a yellow solid from 2g
1
according to the general procedure. 1g: mp decomp.; H NMR (300 MHz,
CD3OD) d 7.59 (s, 1H), 7.34 (s, 1H), 7.13 (d, J ¼ 7.8 Hz, 1H), 6.91
(d, J ¼ 7.8 Hz, 2H), 6.88 (s, 1H), 6.82 (d, J ¼ 7.8 Hz, 1H), 5.70 (s, 1H),
4.02 (s, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.78 (s, 6H); 13C NMR (75 MHz,
CD3OD) d 175.8, 174.9, 150.7, 150.6, 150.4, 149.2, 134.6, 127.3, 127.1,
122.4, 119.0, 116.4, 114.2, 112.9, 110.3, 80.9, 56.6, 56.5, 56.4; HRMS
(FAB) m/z 415.1397 [(M þ H)þ, calcd. for C22H23O8 415.1393].
1h: Compound 1h was prepared in 74% yield as a yellow solid from 2h
1
according to the general procedure. 1h: mp decomp.; H NMR (300 MHz,

1238
E. Kim et al.
CD3OD) d 7.59 (d, J ¼ 2.4 Hz, 1H), 7.03 (s, 2H), 6.64 (s, 2H), 5.60
(d, J ¼ 2.4 Hz, 1H), 3.90 (d, J ¼ 2.4 Hz, 1H), 3.87 (s, 6H), 3.81 (s, 6H),
3.77 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d 177.3, 174.7, 154.8, 154.6,
140.9, 139.9, 139.0, 138.2, 131.4, 125.9, 109.3, 103.6, 84.3, 61.1, 61.0,
56.9, 56.6; HRMS (FAB) m/z 475.1602 [(M þ H)þ, calcd. for C24H27O10
475.1604].
ACKNOWLEDGMENT
This work was supported by a grant from the Plant Diversity Research Center
of 21st Century Frontier Research Program funded by the Ministry of Science
and Technology of the Korean Government.
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