Efficient entry to 1-benzoxepine ring skeleton via tandem SN2/Wittig reaction. Total synthesis of NADH: Ubiquinone oxidoreductase (complex I) antagonist pterulinic acid

Article abstract of DOI:10.1016/S0040-4020(02)01658-7

Concise synthesis of NADH: ubiquinone oxidoreductase (complex I) antagonist pterulinic acid (1a) is reported. The key architectural framework in the natural product, 1-benzoxepine ring skeleton, was smoothly prepared from known salicylaldehyde 2g and phos

Full text of DOI:10.1016/S0040-4020(02)01658-7

Tetrahedron 59 (2003) 1277–1281
Efficient entry to 1-benzoxepine ring skeleton via tandem
SN2/Wittig reaction. Total synthesis of NADH: ubiquinone
oxidoreductase (complex I) antagonist pterulinic acid
*
Yuh-Lin Lin, Hsien-Shou Kuo, Yi-Wen Wang and Sheng-Tung Huang
Department of Biochemistry, Taipei Medical University, 250 Wu Hsing Street, 110 Taipei, Taiwan, ROC
Received 13 November 2002; revised 18 December 2002; accepted 19 December 2002
Abstract—Concise synthesis of NADH: ubiquinone oxidoreductase (complex I) antagonist pterulinic acid (1a) is reported. The key
architectural framework in the natural product, 1-benzoxepine ring skeleton, was smoothly prepared from known salicylaldehyde 2g and
phosphorane 3 via tandem SN2/Wittig reaction. Pterulinic acid was prepared in 5 steps from 2g with overall yield of 25%. The versatility of
tandem SN2/Wittig reaction was investigated. This tandem reaction tolerated various alkyl, ether, tertiaryamine and nitro substituted
salicylaldehyde, and it gave the corresponding 1-benzoxepine ring skeleton in moderated yield (21–72%). q 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
difference between 1a and 1b is the geometric configuration
of the vinyl chloride. The vinyl chloride in pterulinic acid
(1a) takes the Z-configuration. On the other hand, compound
1b bears a vinyl chloride with the E-configuration. Pterulinic
acid (1a and b) was isolated as 1:5 inseparable mixture of
the two isomers (Z)-1a and (E)-1b, respectively. Pterulinic
acid (1a and b) exhibited significant antifungal and weak
or no cytotoxic activity, and it is effective inhibitors of
eukaryotic respiration. The target of the antibiotics resides
within the mitochondrial complex I with an IC50 value of
450 mM.8
NADH: ubiquinone oxidoreductase comprises the first
phosphorylation site of mitochondria and is the energy-
conserving enzyme complex that is commonly known as
‘complex I’.1 There are a wide variety of natural and
synthetic inhibitors of complex I which have found multiple
applications.2 Complex I inhibitors have been used to
elucidate the role of this enzyme in normal cell physiology
and also have been used to mimic complex I deficiencies in
order to study mitochondrial diseases.3 Inhibitors of
complex I have also been a preferred targeted for the
development of commercial insecticides and acaricides for
years.4 Recently, it has been shown that inhibition of
complex I causes concomitant reduction in the activity of
orthine decarboxylase (ODC).5 ODC is responsible for the
biosynthesis of polyamine growth factors required for
cellular prolification.6 Since the overexpression of ODC in
tumor cell contributes to aberrant proliferation, the ability of
complex I inhibitors to reduce ODC activity makes them
promising candidates as next generation antitumor agents.7
Synthesis of pterulinic acid is compelling due to their
complex I antagonist activity, the synthetic challenges
posed by their structure, and their status as potential new
leads in drug discovery efforts. Since only a few 1-
benzoxepin natural products have been previously
reported,10–12 an extensive survey of the literature did not
reveal any efficient methods for the preparation of the 2,3-
dihydro-1-benzoxepine ring skeleton, the architectural
framework resident in 1. As part of a going studies directed
toward the synthetic approach for the preparation of 2,3-
dihydro-1-benzoxepine ring skeleton,13 disclosed herein is
the detail investigation on the versatility of tandem SN2/
Wittig reaction sequence for preparation of 2,3-dihydro-1-
benzoxepine ring skeleton. This approach also applied on
The fungal metabolite pterulinic acid (1a and b) were
isolated from fermentations of a Pterula sp 82168 species.8
The basic architectural framework in pterulinic acid (1a and
1b) is a monochlorinated 2,3-dihydro-1-benzoxepine ring
skeleton containing furan. The structures of 1 was assigned
based on their physical and spectral characteristics.8,9 The
Keywords: pterulinic acid; NADH: ubiquinone oxidoreductase (complex I)
antagonist; tandem SN2/Wittig reaction.
*
Corresponding author. Tel.: þ886-2-2736-1661x3159; fax: þ886-2-
2784-6579; e-mail: ws75624@tmu.edu.tw
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01658-7

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Y.-L. Lin et al. / Tetrahedron 59 (2003) 1277–1281
the first total synthesis of pterulinic acid 1a in 5 steps from
known salicylaldehyde 2g. The tandem SN2/Wittig reaction
sequence demonstrated to be an efficient approach for
preparation of 2,3-dihydro-1-benzoxepine ring skeleton,
and we believe this approach holds promise for providing
future analogues of 1, if desired.
Table 1. Tandem SN2/Wittig reaction of salicylaldehyde 2 and phosphor-
ane 3
Entry
Aldehyde
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
H
Br
O2N
MeO
H
Me
I
H
H
H
H
H
Et2N
H
H
H
H
H
H
H
H
Me
5
6
7
8
53
63
34
65
21
72
68
NR
9
2. Results and discussion
2f
10
11
12
2g15
2h
MOMO
H
The synthesis of pterulinic acid (1) began with the
development of an efficient entry to basic architectural
framework, 2,3-dihydro-1-benzoxepine ring skeletons. We
envisioned the synthesis of 2,3-dihydro-1-benzoxepine ring
skeleton through a tandem reaction sequence that began
with a SN2 ether formation followed by the Wittig
olefination; as resulting from this design, we deduced two
basic starting units, salicylaldehyde 2 and triphenylchloro-
acetonylphosphorane (3)14 (Scheme 1). Treatment of
salicylaldehyde 2 with 1.2 equiv. of sodium ethoxide
generated the corresponding sodium salt of salicylaldehyde;
its subsequent O-alkylation with a-chloroketone 3 produced
4. Intramolecular ring formation via Wittig olefination
between the tethered triphenylacetophosphorane and the
formyl group in 4 gave highly functionalized 5 in 53%
overall yield based on 2.
other hand, the strong electron withdrawing group sub-
stituted on salicylaldehyde (entry 3) also gave low yield for
this reaction. This result could be explained by the
electronic effect on nucleophile in the SN2 reaction. The
strong electron withdrawing group substituted on salicylal-
dehyde polarized the corresponding nucleophile, phenox-
ide, to become more electronegative atom which binds its
electrons more tightly. Since the SN2 process requires
donating of electron density to an antibonding orbital of the
reactant, the high electronegativity is unfavorable;16 as
result, the strong electron withdrawing group substituted on
salicylaldehyde gave the poor yield of this reaction. The
steric hinder effect by the position of the substituents would
also influence this tandem reaction, and this effect was
shown on the ortho substituted salicylaldehyde (entry 8)
which did not give any desired product 12 with only
recovering of starting material.
Upon the success of this tandem reaction for preparation of
5, the versatility of this reaction was investigated. The
results of various salicylaldehyde derivatives reacted with
phosphorane 3 under the same reaction condition to give the
corresponding 2,3-dihydro-1-benzoxepine ring skeleton
were listed in Table 1. This one pot synthesis tolerated
alkyl, ether, tertiaryamine and nitro substituted salicylalde-
hydes, and it smoothly gave the corresponding 2,3-dihydro-
1-benzoxepine ring skeleton in moderated yield (21–72%)
base from the starting salicylaldehyde. The reaction
condition was optimized, and sodium ethoxide in polar
aprotic solvents, DMF or THF, gave the best yield for this
reaction, and the presences of KI with reaction temperature
at 708C were essential conditions for this reaction.
This tandem SN2/Wittig reaction was applied toward the
total synthesis of pterulinic acid. The synthesis of pterulinic
acid (1a) is outlined in Schemes 2 and 3. The synthesis
started with the preparation of benzoxepine-3-one (11) from
known salicylaldehyde 2a.15 The salicylaldehyde 2a under-
went tandem SN2/Wittig reaction with phosphorane 3 to
give 11 in 68% overall yield based on 2a. Removing the
MOM group on 11 with 2N HCl gave o-iodophenol 13 in
99% yield. The o-iodophenol 13 underwent palladium-
catalyzed heteroannulation with methyl 3-butynoate (14)17
to give the tricyclic 15 in 53% yield.18 The synthesis
sequence, tandem SN2/Wittig reaction followed by palla-
dium-catalyzed heteroannulation efficiently constructed
the tricyclic 15 which composed the core structure of the
pterulinic acid and the essential functional handle for the
completion of the synthesis.
The difference in yield of this tandem reaction sequence
with various salicylaldehyde derivatives was influenced by
either electronic or steric factors. The salicylaldehydes
substituted with moderated and weak electron donating
group (entry 4, 6, and 7) gave the best yield for this reaction.
The strong electron donating group substituted on salicyl-
aldehyde (entry 5) gave the lowest yield for this reaction.
The strong electron donating effect by the diethylamine
group induced the corresponding formyl group on 4 to
become more electron rich which resulting less electrophilic
toward the Wittig olefination; therefore, the electron rich
salicylaldehyde gave low yield for this reaction. On the
Next, the vinyl chloride moiety was installed (Scheme 3).
Benzoxepin-3-one 15 was treated with chloromethylphos-
phonium ylide to provide isomer 16 in 86% yield with
.20:1 Z/E selectivity, and the final assignment of the
configuration for purified (Z)-16 was determined by NOE
and 2D-heteronuclear correlation experiments. Finally,
hydrolysis of the methyl ester 16 under basic condition
Scheme 1.

Y.-L. Lin et al. / Tetrahedron 59 (2003) 1277–1281
1279
Scheme 2. Conditions: (a) EtONa, KI, THF, 3 reflux, 68%; (b) 2N HCl, THF, rt, 99%; (c) 10 mol% (Ph3P)2PdCl2, 1.9 equiv. CuI, 1.6 equiv. Et3N, DMF, 608C,
53%.
followed by acidic work up gave pterulinic acid (1a) in 83%
yield. The spectral and physical characteristics (IR, 1H
NMR, 13C NMR, and MS) of synthetic 1a were identical to
the published data.8
FT-IR system. Silica gel TLC was performed on 60F-254
pre-coated sheets (E. Merck) and column chromatography
was done on silica gel (60–120 mesh). All of chemicals
were used directly as purchased from Acros, Aldrich, or TCI
unless otherwise noted.
3. Conclusion
4.2. General procedure for the synthesis of 2,3-dihydro-
1-benzoxepine ring skeleton
The aim of the present study provides the first insight in the
manner in which different types of substituted salicylalde-
hyde undergoes tandem SN2/Wittig reaction with phosphor-
ane 3. In addition, this one-pot, tandem SN2/Wittig reaction
of salicylaldehyde and phosphorane 3 allows for the easy
introduction of 2,3-dihydro-1-benzoxepine ring skeleton.
The total synthesis reported herein provides pterulinic acid
1a in 5 steps with overall yield of 25% base on the
salicylaldehyde 2g. This new synthetic application had
demonstrated to be an efficient approach toward the total
synthesis of natural product, pterulinic acid. A synthesis of
this type, if reduced to practice, promised to provide ready
access to 1a and analogue thereof.
The freshly prepared sodium ethoxide (2.40 mmol) were
added at 08C to a well stirred solution of appropriated
salicylaldehyde (2.00 mmol) and KI (3.00 mmol) in anhy-
drous THF (2 mL) under nitrogen atmosphere. After the
resulting suspension was stirred at 08C for 1 h, the a-
chlorotriphenylacetophosphorane (3) (3.00 mmol) was
added into suspension under nitrogen atmosphere. The
corresponding reaction mixture was stirred at 708C for 12 h;
the solvent was removed under reduced pressure. Then, the
mixture was diluted with ethyl acetate and washed with 1N
HCl and water. The organic extract was dried (MgSO4) and
concentrated under reduced pressure. Chromatography of
the residue eluting with ethyl acetate/hexanes mixture gave
analytically pure compounds. Spectroscopic and analytical
data of benzoxepin-3-one follow.
4. Experimental
4.1. General
4.2.1. Benzo[b]oxepin-3-one (5). From 200.0 mg of
salicylaldehyde 2a, 142.3 mg (53%) of compound 5 was
obtained as yellow oil after purification by flash chromato-
graphy (hexanes/ethyl acetate 4:1). 1H NMR: d 4.54 (s, 2H),
6.35 (d, 1H, J¼12.1 Hz), 7.14 (m, 2H), 7.18 (d, 1H,
J¼12.1 Hz), 7.34–7.37 (m, 2H). 13C NMR: d 77.8, 120.8,
124.3, 127.5, 129.2, 132.2, 133.4, 142.2, 160.0, 196.9. IR
(oil, cm21): n 2978, 1667. MS (EI) m/z: 160. Anal. calcd for
C10H8O2: C, 74.99; H, 5.03. Found: C, 74.95; H, 5.08.
Proton and carbon NMR were obtained on a Bruker AMX-
500 spectrometer. NMR spectra were recorded in CDCl3
solution, expect as otherwise stated. Chemical shifts were
reported in ppm relative to tetramethylsilane (d units). Fast
atom bombardment (FAB) mass spectra and elemental
analyses were recorded on a Micromass ZAB spectrometer
and Perkin–Elmer 2400 elemental analyzer repetitively at
the Analytical Facility of The National Taiwan University.
IR spectra were obtained on Perkin–Elmer Spectrum RXI
4.2.2. 7-Bromo-benzo[b]oxepin-3-one (6). From 200.2 mg
Scheme 3. Conditions: (a) n-BuLi, Ph3PCH2Cl2, THF, rt, 86%; (b) 0.5 M NaOH, MeOH, then HCl, 83%.

1280
Y.-L. Lin et al. / Tetrahedron 59 (2003) 1277–1281
of salicylaldehyde 2b, 161.3 mg (66%) of compound 6 was
obtained as yellow solid after purification by flash
chromatography (hexanes/ethyl acetate 4:1). Mp 104–
by flash chromatography (hexanes/ethyl acetate 10:1). Mp
109–1108C (hexane/ethyl acetate). 1H NMR: d 3.50 (s,
J¼3 Hz), 4.52 (s, 2H), 5.25 (s, 2H), 6.25 (d, 1H,
J¼12.1 Hz), 6.86 (s, 1H), 7.03 (d, 1H, J¼12.1 Hz), 7.77
(s, 1H). 13C NMR: d 56.7, 77.7, 80.2, 94.9, 106.6, 123.3,
127.9, 140.7, 143.3, 158.5, 160.6, 195.8. IR (KBr, cm21): n
2918, 1651. MS (EI) m/z: 346. Anal. calcd for C12H11IO4:
C, 41.64; H, 3.20. Found: C, 41.55; H, 3.09.
1
1058C (hexane/ethyl acetate). H NMR: d 4.52 (s, 2H),
6.37 (d, 1H, J¼12.1 Hz), 7.02 (d, 1H, J¼8.6 Hz), 7.07 (d,
1H, J¼12.1 Hz), 7.44 (dd, 1H, J¼8.6, 2.4 Hz), 7.50 (d, 1H,
J¼2.4 Hz). 13C NMR: d 79.7, 116.8, 122.6, 129.2, 130.3,
134.8, 135.4, 140.4, 158.0, 196.2. IR (KBr, cm21): n 1664.
MS (EI) m/z: 239. Anal. calcd for C10H7O2Br: C, 50.24; H,
2.95. Found: C, 50.19; H, 2.99.
4.2.8. 8-Hydroxy-7-iodo-benzo[b]oxepin-3-one (13). A
solution of the benzo[b]oxepin-3-one 11 (1.73 g, 5 mmol)
and 0.1 mL of conc. HCl in 5 mL of EtOH was stirred at
reflux temperature for 2 h. The mixture was diluted with
ethyl acetate and washed with water. The organic extract
was dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue eluting with
ethyl acetate/hexanes mixture gave 1.47 g (99%) of a
yellow solid. Mp 154–1558C (hexane/ethyl acetate). 1H
NMR: d 4.54 (s, 1H), 5.58 (s, 1H), 6.27 (d, J¼12.0 Hz), 6.80
(s, 1H), 7.05 (d, J¼12.0 Hz), 7.69 (s, 1H). 13C NMR: d 77.7,
79.4, 107.1, 123.0, 127.7, 140.6, 142.4, 157.7, 161.1, 195.9.
IR (KBr, cm21): n 2918, 1651. MS (EI) m/z: 302. Anal.
calcd for C10H7IO3: C, 39.76; H, 2.34. Found: C, 39.59; H,
2.50.
4.2.3. 7-Nitro-benzo[b]oxepin-3-one (7). From 200.0 mg
of salicylaldehyde 2c, 84.3 mg (34%) of compound 7 was
obtained as yellow solid after purification by flash
chromatography (hexanes/ethyl acetate 3:1). Mp 128–
1
1298C (hexane/ethyl acetate). H NMR: d 4.62 (s, 2H),
6.50 (d, 1H, J¼12.1 Hz), 7.22 (d, 1H, J¼12.1 Hz), 7.28 (d,
1H, J¼8.9 Hz), 8.21 (dd, 1H, J¼8.9, 2.7 Hz), 8.31 (d, 1H,
J¼2.7 Hz). 13C NMR: d 77.6, 122.0, 126.9, 127.4, 128.8,
131.3, 139.8, 144.0, 163.3, 194.5. IR (KBr, cm21): n 1667.
MS (EI) m/z: 205. Anal. calcd for C10H7NO4: C, 58.54; H,
3.44; N, 6.83. Found: C, 58.51; H, 3.46; N, 6.80.
4.2.4. 7-Methoxy-benzo[b]oxepin-3-one (8). From
100.0 mg of salicylaldehyde 2d, 81.4 mg (65%) of com-
pound 8 was obtained as yellow solid after purification by
flash chromatography (hexanes/ethyl acetate 5:1). Mp 35–
4.2.9. (7-Oxo-7,8-dihydro-1,9-dioxa-cyclohepta[f]
inden-2-yl)-acetic acid methyl ester (15). To a well-
stirred mixture of o-iodophenol 13 (151.0 mg, 0.5 mmol),
Pd(Ph3P)2Cl2 (35.1 mg, 0.05 mol), CuI (183.1 mg,
0.95 mmol) and triethylamine (0.11 mL, 0.8 mmol) in
anhydrous DMF (2 mL), methyl 3-butynoate (14)
(130.1 mg, 1.25 mmol) was added under a N2 atmosphere.
The mixture was stirred at 608C for 16 h. The mixture was
cooled, diluted with ethyl acetate and washed with 1N
NaOH and water. The organic extract was dried (MgSO4)
and concentrated under reduced pressure. Chromatography
of the residue eluting with ethyl acetate/hexanes 1:4 mixture
gave 72.1 mg (53%) of 15 as off yellow solid. Mp 110–
1118C (hexane/ethyl acetate). 1H NMR: d 3.77 (s, 3H), 3.83
(s, 2H), 4.58 (s, 2H), 6.32 (d, 1H, J¼12.1 Hz), 6.83 (s, 1H),
7.24 (s, 1H), 7.27 (d, 1H, J¼12.1 Hz), 7.53 (s, 1H). 13C
NMR: d 34.2, 52.5, 78.3, 103.6, 104.9, 124.2, 125.0, 125.5,
127.6, 142.7, 152.4, 156.2, 156.7, 168.9, 197.4. MS (EI)
m/z: 272. Anal. calcd for C15H12O5: C, 66.17; H, 4.44.
Found: C, 66.10; H, 4.54.
1
378C (hexane/ethyl acetate). H NMR: d 3.79 (s, 3H), 4.50
(s, 2H), 6.34 (d, 1H, J¼12.1 Hz), 6.84 (d, 1H, J¼2.9 Hz),
6.89 (dd, 1H, J¼8.8, 2.9 Hz), 7.06 (d, 1H, J¼8.8 Hz), 7.11
(d, 1H, J¼12.1 Hz). 13C NMR: d 55.8, 78.2, 116.8, 117.9,
121.6, 128.1, 129.6, 141.8, 152.9, 155.9, 197.4. IR (KBr,
cm21): n 2917, 1667. MS (EI) m/z: 190. Anal. calcd for
C11H10O3: C, 69.46; H, 5.30. Found: C, 69.55; H, 5.20.
4.2.5. 8-Diethylamino-benzo[b]oxepin-3-one (9). From
200.0 mg of salicylaldehyde 2e, 49.3 mg (21%) of com-
pound 9 was obtained as yellow solid after purification by
flash chromatography (hexanes/ethyl acetate 3:1). Mp 72–
748C (hexane/ethyl acetate). 1H NMR: d 1.14 (t, 3H,
J¼6.6 Hz), 3.38 (q, 2H, J¼6.6 Hz), 4.50 (s, 2H), 6.34 (d,
1H, J¼12.1 Hz), 6.84 (d, 1H, J¼2.9 Hz), 6.89 (dd, 1H,
J¼8.8, 2.9 Hz), 7.06 (d, 1H, J¼8.8 Hz), 7.11 (d, 1H,
J¼12.1 Hz). 13C NMR: d 55.8, 78.2, 116.8, 117.9, 121.6,
128.1, 129.6, 141.8, 152.9, 155.9, 197.4. IR (KBr, cm21): n
2917, 1667. MS (EI) m/z: 231 (M). Anal. calcd for
C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.59;
H, 7.33; N, 5.99.
4.2.10. 7-Chloromethylene-7,8-dihydro-1,9-dioxa-cyclo-
hepta[f]inden-2-yl)-acetic acid methyl ester (16). The n-
BuLi (0.25 mmol) were added at 08C to a well stirred
solution of (chloromethyl)triphenylphosphonium chloride
(90.27 mg, 0.26 mmol) in anhydrous THF (1 mL) under
nitrogen atmosphere. After the resulting suspension was
stirred at 08C for 30 min, the enone 15 (23.93 mg,
0.088 mmol) in anhydrous THF (1 mL) was added dropwise
into mixture under nitrogen atmosphere at 08C. The
corresponding reaction mixture was stirred at 08C for 1 h.
Then, the mixture was quenched with 1N HCl at 08C and
extracted with ethyl acetate. The combine organic extract
was dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue eluting with
ethyl acetate/hexanes (1:5) mixture gave 23.1 mg (86%)
of off yellow solid. Mp 65–678C (hexane/ethyl acetate). 1H
NMR: d 3.75 (s, 3H), 3.81 (s, 2H), 4.91 (s, 2H), 6.28 (s, 1H),
4.2.6. 7-Methyl-benzo[b]oxepin-3-one (10). From 200.0 mg
of salicylaldehyde 2f, 185.2 mg (72%) of compound 9 was
obtained as yellow oil after purification by flash chromato-
graphy(hexanes/ethyl acetate 3:1). 1H NMR: d 2.32 (s,
J¼3 Hz), 4.50 (s, 2H), 6.32 (d, 1H, J¼12.1 Hz), 7.02 (d, 1H,
J¼12.1 Hz), 7.11-7.15 (m, 3H). 13C NMR: d 20.5, 77.9,
120.4, 127.1, 129.1, 132.9, 133.5, 133.8, 142.3, 156.9,
197.1. IR (KBr, cm21): n 2917, 1667. MS (EI) m/z: 174.
Anal. calcd for C11H10O2: C, 75.84; H, 5.79. Found: C,
75.77; H, 5.66.
4.2.7. 7-Iodo-8-methoxymethoxy-benzo[b]oxepin-3-one
(11). From 2.76 g of salicylaldehyde 2g, 2.16 g (68%) of
compound 11 was obtained as yellow solid after purification

Y.-L. Lin et al. / Tetrahedron 59 (2003) 1277–1281
1281
2. Degli Esposti, M. Biochim. Biophys. Acta 1995, 1271, 1–292.
3. Barrientos, A.; Moraes, C. T. J. Biol. Chem. 1999, 274,
16188–16197.
6.27 (d, 1H, J¼11.5 Hz), 6.43 (d, 1H, J¼11.5 Hz), 6.56 (s,
1H), 7.13 (s, 1H), 7.34 (s, 1H). 13C NMR: d 29.7, 52.4, 69.2,
103.0, 104.8, 120.0, 123.3, 124.6, 124.8, 126.1, 128.5,
138.9, 151.3, 154.9, 157.1, 169.2. IR (KBr, cm21): n 2920,
1744. MS (EI) m/z: 304. Anal. calcd for C16H13ClO4: C,
63.06; H, 4.30. Found: C, 63.16; H, 4.51.
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4.2.11. Pterulinic acid (1a). To a stirred solution of ester 16
(10.0 mg, 0.033 mmol) in MeOH (1 mL) in ice bath, 5 mL
of 0.5 M NaOH was added. The mixture was stirred at 08C
for 1 h. The mixture was diluted with water and washed with
ethyl acetate. The basic aqueous layer was neutralized with
concentrated HCl at 08C. The corresponding aqueous layer
was extracted with ethyl acetate. The organic extract was
dried (MgSO4) and concentrated under reduced pressure.
The crude residue was recrystallized with chloroform/
hexanes to give 8.3 mg (83%) of 1a as yellow solid. Mp
165–1678C (chloroform/hexane). 1H NMR (CDCl3:CD3OD
95:5): d 3.74 (s, 2H), 4.86 (s, 2H), 6.24 (s, 1H), 6.23 (d, 1H,
J¼11.5 Hz), 6.38 (d, 1H, J¼11.9 Hz), 6.52 (s, 1H), 7.08 (s,
1H), 7.30 (s, 1H). 13C NMR (CDCl3/CD3OD 95:5): d 34.3,
69.1, 102.9, 104.6, 118.9, 123.3, 124.6, 124.7, 125.9, 128.4,
138.8, 151.8, 154.7, 156.8, 171.0. IR (KBr, cm21): n 3435,
2920, 1698. MS (EI) m/z: 290. Anal. calcd for C15H11O4Cl:
C, 61.98; H, 3.81. Found: C, 61.77; H, 3.92.
7. Udeani, G. O.; Gerhauser, C.; Thomas, C. F.; Moon, R. C.;
Kosmeder, J. W.; Kinghorn, A. D.; Moriarty, R. M.; Pezzuto,
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Acknowledgements
We gratefully acknowledge the National Science Council
(NSC 91-2113-M-038-002) for financial support.
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