Synthesis of 4-acetylisocoumarin: First total syntheses of AGI-7 and sescandelin

Article abstract of DOI:10.1021/jo010789b

A practical synthetic route to 4-acetylisocoumarins and the first total synthesis of AGI-7 (5) and sescandelin (4) are described. The readily available homophthalate 8 was transformed to the vinylogous amide ester 13 in high overall yield. Upon treatment of 13 with refluxing aqueous formic acid, the desired 4-acetylisocoumarin (5) and its regioisomer 3-methyl-4-formylisocoumarin (17) were produced in a 3:1 ratio. After separation of the desired product (5) from the unwanted minor isomer, the enantioselective reduction of AGI-7 by borane in the presence of Corey's (S)-oxazaborolidine reagent afforded (+)-sescandelin (4) with a 93% ee.

Full text of DOI:10.1021/jo010789b

J . Org. Chem. 2002, 67, 3127-3130
3127
Syn th esis of 4-Acetylisocou m a r in : F ir st
Tota l Syn th eses of AGI-7 a n d Sesca n d elin
Sanghee Kim,*,†,‡ Gao-jun Fan,†,‡ J aekwang Lee,†
J ung J oon Lee,§ and Deukjoon Kim‡
Natural Products Research Institute, Seoul National
University, 28 Yungun, J ongro, Seoul 110-460, Korea,
College of Pharmacy, Seoul National University, San 56-1,
Shilim, Kwanak, Seoul 151-742, Korea, and Korea Research
Institute of Bioscience and Biotechnology P.O. Box 115,
Yusong, Taejon 305-600, Korea
pennkim@snu.ac.kr
Received August 3, 2001
Abstr a ct: A practical synthetic route to 4-acetylisocou-
marins and the first total synthesis of AGI-7 (5) and
sescandelin (4) are described. The readily available homo-
phthalate 8 was transformed to the vinylogous amide ester
13 in high overall yield. Upon treatment of 13 with refluxing
aqueous formic acid, the desired 4-acetylisocoumarin (5) and
its regioisomer 3-methyl-4-formylisocoumarin (17) were
produced in a 3:1 ratio. After separation of the desired
product (5) from the unwanted minor isomer, the enanti-
oselective reduction of AGI-7 by borane in the presence of
Corey’s (S)-oxazaborolidine reagent afforded (+)-sescandelin
(4) with a 93% ee.
F igu r e 1. 4-Substituted 3-nonsubstituted natural isocou-
marins.
reported that these isocoumarin compounds possess
various interesting bioactivities including root-promoting
activity and antibiotic activities against plant cells,
bacteria, and plant-pathogenic fungi.7,9,10
In the screening of anti-angiogenic substances inhibit-
ing differentiation of endothelial cells to a capillary-like
structure on Matrigel, one of us isolated a new compound,
6,8-dihydroxy-4-acetylisocoumarin, which was named
AGI-7 (5), along with sescandelin (4) from an unidentified
fungal strain by bioassay-guided fractionation and isola-
tion.11 To further investigate the biochemical and phar-
maceutical effects of sescandelin and AGI-7, especially
in growth and proliferation of new blood vessels, we
needed to synthesize these isocoumarins in large quanti-
ties. Herein, we report a practical and high-yielding
synthetic route to 4-acetylisocoumarins and the first total
syntheses of AGI-7 (5) and sescandelin (4).
Among the naturally occurring isocoumarin deriva-
tives, 4-substituted isocoumarins with no substituent at
the 3-position are very rare,1 and only a few synthetic
methods for construction of the skeleton have been
developed.2-5 Ray3 synthesized 4-methylisocoumarin by
cyclization of acetonyl benzoate in sulfuric acid, and
Usgaonkar4 reported the synthesis of 4-carboxyisocou-
marin from homophthalic acid with DMF-POCl3. 4-Ace-
tylisocoumarins have been prepared from 4-carboxyiso-
coumarins by addition of magnesium malonate to the
corresponding acid chloride followed by hydrolysis in poor
to modest overall yields.5
The synthesis began from known homophthalate 812
(Scheme 1), which was synthesized as described previ-
ously.12b Diels-Alder reaction of diene 6 and allenedi-
carboxylate 7, followed by aromatization with Et3NH+F-,
provided 8 in 69% yield. Protection of the phenol 8 as its
dibenzyl ether 9 and basic hydrolysis of diester provided
homophthalic acid 10 in 81% yield. A facile two-step
transformation of homophthalic acid 10 to ketone 11 was
conducted by employing literature procedure.13 Reaction
of 10 with acetic anhydride/pyridine followed by hydroly-
sis with aqueous sodium hydroxide gave ketone 11 in 76%
Some representative 4-substituted 3-nonsubstituted
natural isocoumarins are oospoglycol (1),6 oosponol (2),7
4-acetyl-6,8-dihydroxy-5-methylisocoumarin (3),8 and (-)-
sescandelin (4)1,9 as shown in Figure 1. It has been
* To whom correspondence should be addressed. Phone: +82-2-740-
8913. Fax: +82-2-762-8322
† Natural Products Research Institute.
‡ College of Pharmacy.
§ Korea Research Institute of Bioscience and Biotechnology.
(1) Kimura, Y.; Nakadoi, M.; Shimada, A.; Nakajima, H.; Hamasaki,
T. Biosci. Biotechnol. Biochem. 1994, 58, 1525.
1
yield. The H NMR spectrum of 11 at room temperature
showed two extremely broad singlets (δ 4.1-3.9 for the
ArCH2COCH3 protons and δ 2.4-2.2 for the ArCH2-
COCH3 protons). In contrast, that of methyl ester of 11
showed sharp singlets at δ 3.64 and 2.08. Two broad
signals of 11 appeared at further downfield compare to
the corresponding signals of methyl ester of 11. This
(2) For recent review on the synthesis of isocoumarins, see: Na-
politano, E. Org. Prep. Proced. Int. 1997, 29, 633.
(3) Arora, P. K.; Ray, S. J . Indian Chem. Soc. 1985, LXII, 383.
(4) (a) Belgaonkar, V. H.; Usgaonkar, R. N. J . Chem. Soc., Perkin
Trans. 1 1977, 702. (b) Belgaonkar, V. H.; Usgaonkar, R. N. Chem.
Ind. (London) 1976, 954.
(5) (a) Kimura, M.; Waki, I.; Deguchi, Y.; Amemiya, K.; Maeda, T.
Chem. Pharm. Bull. 1983, 31, 1277. (b) Kokubo, M.; Kimura, M.; J apan
patent 8035, 1967; Chem. Abstr. 1967, 67, 116818k.
(6) Nitta, K.; Yamamoto, Y.; Yamamoto, I.; Yamatodani, S. Agric.
Biol. Chem. 1963, 27, 822.
(9) Kimura, Y.; Nakajima, H.; and Hamasaki, T. Agric. Biol. Chem.
1990, 54, 2477.
(7) (a) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.; Nakaima, S.
Chem. Pharm. Bull. 1981, 29, 2689. (b) Nitta, K.; Imai, J .; Yamamoto,
I.; Yamamoto, Y. Agric. Biol. Chem. 1963, 27, 817. (c) Nakajima, S.;
Kawai, K.; Yamada, S. Phytochemistry 1976, 15, 327.
(8) Aldrige, D. C.; Grove, J . F.; Turner, W. B. J . Chem. Soc. C 1966,
126.
(10) Kovacs, M.; Sonnenbichler, J . Liebigs Ann. Chem. 1997, 211.
(11) Lee, J . H.; Park, Y. J .; Kim, H. S.; Hong, Y. S.; Kim, K.-W.;
Lee, J . J . J . Antibiot. 2001, 54, 463.
(12) (a) Singh, S.; Singh, I. Indian J . Chem. 1985, 24B, 568. (b)
Roush, W. R.; Murphy, M. J . Org. Chem. 1992, 57, 6622.
(13) Hauser, F. M.; Rhee, R. P. J . Org. Chem. 1977, 42, 4155.
10.1021/jo010789b CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/29/2002

3128 J . Org. Chem., Vol. 67, No. 9, 2002
Notes
Sch em e 1a
in a 1.5:1 ratio with a combined yield of 95%. Prolonged
reaction times did not change the product ratio. In
refluxing 70% aqueous acetic acid, compound 13 gave a
2:1 mixture of 16 and 15 in 95% crude yield. These
intramolecular cycloadducts were perhaps formed via the
intermediate 14, which could be observed in the crude
1H NMR spectrum obtained from the reaction mixture
in 10 min at refluxing temperature or 20 min at 60 °C.
When the acetic acid was replaced by formic acid, the
selectivity in favor of 4-acetylisocoumarin was increased.
The condition of refluxing 70% aqueous formic acid
effected the intramolecular cyclization and concomitant
deprotection of the benzyl protecting groups to afford a
3:1 mixture of 5 and 17. Change of formic acid concentra-
tion from 70% to 50% or 90% did not alter the product
ratio significantly.
Unfortunately, the separation of the desired product
(5 and 16) from the unwanted minor isomer (17 and 15)
was not an easy task. To circumvent this problem, the
crude mixture of 5 and 17 was treated with J ones reagent
to oxidize the aldehyde functional group of minor 15 to
the carboxylic acid.15 This treatment enabled the efficient
a
Reagents and conditions: (a) neat, 0-25 °C, 70 min, then
Et3NHF, EtOH, rt, 40 min, 69%; (b) BnBr, K2CO3, acetone, KI,
reflux, 2 days, 87%; (c) KOH, EtOH, H2O, reflux, 24 h, 93%; (d)
Ac2O, pyr, Et2O, rt, overnight; (e) 10% aq NaOH, H2O, 60 °C, 1 h,
76% from 10; (f) dimethylchloromethyleneammonium chloride,
DMF, rt; or POCl3, DMF, rt; (g) N,N-dimethylformamide dimethyl
acetal, toluene, reflux, 5 h, 87%; (h) 70% aq AcOH, reflux, 5 h,
95% as a mixture of 16 and 15 (2:1); (i) 70% aq HCO2H, reflux, 1
day, see text.
purification of AGI-7 (5) and did not affect the final
isolated yield (56%) considerably. It is noteworthy that
exposure of the purified 5 to 50% aqueous formic acid (7
h at refluxing temperature) led to a 3:1 regioisomeric
mixture of 5 and 17 in almost quantitative yield (eq 1).
This result suggested that the observed product distribu-
tion ratio during the intramolecular cyclization of 13
would be reflective of the thermodynamic equilibrium of
the products under acidic conditions. Furthermore, the
coexistence of sescandelin B (18) (eq 1), which has the
same carbon numbers and an isocoumarin skeleton with
sescandelin, implied that formation of both regioisomer
5 and 17 could also occur in the biosynthesis.1,16
phenomenon suggests that the carboxylic acid group
forms an intramolecular hydrogen bond with the neigh-
boring ketone oxygen atom in compound 11.
With 11 in hand, we set out to explore formation of
the 4-acetyl-3-nonsubstituted isocoumarin ring system.
The initial attempts to obtain compound 16 using Vils-
meier reagents gave only 3-methylisocoumarin 12 with-
out formation of the desired product. However, treatment
of 11 with commercially available N,N-dimethylforma-
mide dimethyl acetal in refluxing toluene effected the
introduction of the vinylogous amide functionality14 and
concomitant esterification of carboxylic acid residue to
afford 13 in 87% yield as a single compound. NOE
difference experiments indicated that the stereochemistry
of vinylogous amide was E as shown in Scheme 1.
Our attempts to prepare target the 4-acetylisocoumarin
ring system from 13 began with acetic acid as an acid
reaction solvent. Upon treatment of 13 with refluxing
glacial acetic acid for 5 h, the desired 6,8-dibenzyloxy-
4-acetylisocoumarin (16) and its regioisomer 6,8-diben-
zyloxy-3-methyl-4-formylisocoumarin (15) were produced
Finally, AGI-7 (5) was reduced under Luche condi-
tions17 to provide (()-sescandelin (4) as a racemate in
1
96% yield, of which H and 13C NMR spectral data were
in good agreement with those reported1,9,11 The enantio-
selective reduction of the carbonyl of AGI-7 (5) to the
corresponding alcohol was achieved by using Corey’s
oxazaborolidine-catalyzed reduction.18 Reduction of the
ketone 5 by borane in the presence of 20 mol % of the
(S)-oxazaborolidine reagent afforded (+)-sescandelin (4)
(15) Israel, R. J .; Murray, R. K. J r. J . Org. Chem. 1985, 50, 4703.
(16) The feeding experiments with 13C-labeled compounds indicated
that sescandelin and sescandelin B have been biosynthesized from the
same carbon origin; see ref 1.
(14) Dominguez, E.; Marigorta, E. M. D.; Olivera, R.; SanMartin,
R. Synlett 1995, 955.
(17) Luche, J .-L. J . Am. Chem. Soc. 1978, 100, 2226.
(18) Corey, E. J .; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611.

Notes
J . Org. Chem., Vol. 67, No. 9, 2002 3129
in 88% yield with a 93% ee.19 The observed optical
(20 mL) and was heated at 60 °C. To it was added dropwise 10%
aqueous NaOH solution. The solid was quickly dissolved, and
additional sodium hydroxide solution was added until pH 11.
Heating and stirring were continued for an additional 0.5 h.
Then, the solution was acidified to pH 2 with 10% aqueous HCl.
After cooling, the cloudy reaction solution was extracted with
EtOAc four times. The combined organic layers were dried over
anhydrous Na2SO4, filtered, and evaporated under reduced
pressure. The resulting solid was further purified by flash
chromatography (hexanes/EtOAc ) 1:1, then 100% EtOAc) to
afford 681 mg of 11 (76%) as a gray solid: Rf ) 0.38 (100%
EtOAc); mp 134-136 °C; 1H NMR (CDCl3, 300 MHz) δ 2.2-2.4
(br s, 3H), 3.9-4.1 (br s, 2H), 5.07 (s, 2H), 5.17 (s, 2H), 6.50 (br
s, 1H), 6.67 (br s, 1H), 7.32-7.45 (m, 10H); 13C NMR (CDCl3,75
MHz) δ 205.5, 165.8, 162.1, 159.6, 142.5, 135.7, 134.4, 129.0,
128.7, 128.4, 127.8, 127.5, 112.8, 111.9, 100.0, 72.4, 70.3, 50.6,
29.9; IR (KBr) νmax 3414, 1718, 1604, 1167 cm-1; HRMS calcd
for C24H22O5 (M+) 390.1467, found 390.1419. Anal. Calcd for
rotation for (+)-4 [[R]21 ) +31.6 (c 0.02, MeOH)] was
D
comparable in magnitude and opposite in sign to the
literature value9 for naturally occurring (-)-4 [[R]D ) -33
(c 1.0, MeOH)].
In conclusion, the chemistry described herein provides
a practical synthetic method of 4-acetylisocoumarin syn-
thesis, and we were able to accomplish a total synthe-
sis of the nonnatural (+)-sescandelin (4) and AGI-7 (5)
in high overall yield. Further application of this meth-
odology to various types of 4-substituted isocoumarin
synthesis is now under investigation in this laboratory.
Exp er im en ta l Section
Gen er a l Meth od s. All chemicals were reagent grade and
used as purchased. All reactions were performed under an inert
atmosphere of dry argon or nitrogen using distilled dry solvents.
Reactions were monitored by TLC analysis using silica gel thin
layer plates. Flash column chromatography was carried out on
silica gel (230-400 mesh). Melting points are uncorrected.
Optical rotations were measured using sodium light (D line 589.3
nm).
C
24H22O5: C, 73.83; H, 5.68. Found: C, 74.08; H, 5.85.
2-(1-Acetyl-2-(d im eth yla m in o)vin yl)-4,6-bis-ben zyloxy-
ben zoic Acid Meth yl Ester (13). To acid 11 (390 mg, 1.0 mmol)
in toluene (50 mL) was added N,N-dimethylformamide dimethyl
acetal (1.33 mL, 10.0 mmol) slowly under argon. The resulting
mixture was heated to reflux for 5 h. After reaction, the toluene
was evaporated under reduced pressure, and the subsequent
residue was subjected to column chromatography (100% EtOAc)
to give 400 mg (87%) of pure 13 as a yellow oil: Rf ) 0.27 (100%
EtOAc); 1H NMR (CDCl3, 300 MHz) δ 1.90 (s, 3H), 2.62-2.78
(br s, 6H), 3.75 (s, 3H), 5.05 (s, 2H), 5.09 (s, 2H), 6.40 (d, J ) 2.1
Hz, 1H), 6.56 (d, J ) 2.4 Hz, 1H), 7.26-7.41 (m, 10H), 7.54 (s,
1H); 13C NMR (CDCl3, 75 MHz) δ 195.5, 168.1, 159.5, 156.4,
149.0, 138.9, 136.4, 136.3, 128.6, 128.4, 128.1, 127.8, 127.4, 126.9,
120.5, 110.6, 107.0, 100.2, 70.4, 70.1, 52.0, 42.6, 27.3; IR (KBr)
νmax 1730, 1653, 1597, 1564, 1269, 1157 cm-1; HRMS calcd for
2,4-Bis-ben zyloxy-6-m eth oxycar bon ylm eth ylben zoic Acid
Meth yl Ester (9). A mixture of homophthalate 812 (2.20 g, 9.16
mmol), K2CO3 (8.20 g, 59.33 mmol), KI (1.64 g, 9.88 mmol), and
excess benzyl bromide (7.0 mL, 58.85 mmol) in acetone (60 mL)
was refluxed for 2 days with stirring. After the mixture was
cooled to room temperature, solid K2CO3 was filtered off. The
filtrate was concentrated in vacuo. The subsequent residue was
diluted with EtOAc (100 mL) and washed with 1 N aqueous HCl
two times and water two times. The organic layer was dried
(MgSO4) and evaporated under vacuum. The residue was
purified by column chromatography (hexanes/EtOAc ) 4:1) to
afford 3.35 g (87%) of 9 as a light yellow solid: Rf ) 0.32
(hexanes/EtOAc ) 3:1); mp 84-85 °C; 1H NMR (CDCl3, 300
MHz) δ 3.69 (s, 3H), 3.70 (s, 2H), 3.86 (s, 3H), 5.04 (s, 2H), 5.07
(s, 2H), 6.52 (d, J ) 2.4 Hz, 1H), 6.54 (d, J ) 2.4 Hz, 1H), 7.30-
7.41 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 171.2, 167.6, 160.8,
158.1, 136.5, 136.3, 135.2, 128.6, 128.5, 128.2, 127.8, 127.5, 126.9,
116.7, 109.0, 100.1, 70.6, 70.2, 52.0, 51.9, 39.5; IR (KBr) νmax
1736, 1705, 1606, 1167 cm-1; HRMS calcd for C25H24O6 (M+)
420.1573, found 420.1584. Anal. Calcd for C25H24O6: C, 71.41;
H, 5.75. Found: C, 71.54; H, 5.82.
2,4-Bis-ben zyloxy-6-ca r boxym eth ylben zoic Acid (10). A
mixture of ester 9 (3.0 g, 7.14 mmol), KOH (2.41 g, 43.0 mmol),
EtOH (60 mL), and water (20 mL) was refluxed for 24 h. After
being cooled to room temperature, the solution was acidified
with 1 N aqueous HCl to pH 2 and then extracted with EtOAc
three times. The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and evaporated under
reduced pressure. After purification by short flash chromatog-
raphy using EtOAc, 2.61 g (93%) of 10 was obtained as a light
yellow solid: Rf ) 0.23 (EtOAc/CH3OH ) 4:1); mp 157-158 °C;
1H NMR (CD3OD, 300 MHz) δ 3.71 (s, 2H), 5.05 (s, 2H), 5.09 (s,
2H), 6.58 (d, J ) 2.1 Hz, 1H), 6.64 (d, J ) 2.4 Hz, 1H), 7.28-
7.44 (m, 10H); 13C NMR (CD3OD, 75 MHz) δ 174.6, 171.2, 162.2,
159.1, 138.2, 138.1, 137.0, 129.5, 129.4, 129.0, 128.8, 128.7, 128.3,
118.5, 110.7, 100.8, 71.7, 71.2, 40.3; IR (KBr) νmax 3429, 1716,
1604, 1172 cm-1; HRMS calcd for C23H20O6 (M+) 392.1260, found
392.1231. Anal. Calcd for C23H20O6: C, 70.40; H, 5.14. Found:
C, 70.67; H, 5.33.
C
28H29NO5 (M+) 459.2046, found 459.2043. Anal. Calcd for
C28H29NO5: C, 73.08; H, 6.31; N, 2.98. Found: C, 73.09; H, 6.31;
N, 2.98.
4-Acetyl-6,8-bis-ben zyloxyisoch r om en -1-on e (16). The vi-
nylogous amide ester 13 (2.1 g, 4.57 mmol) was refluxed in 70%
aqueous acetic acid (70 mL) for 5 h. It was concentrated under
reduced pressure. The residue was treated with EtOAc and then
washed with brine, saturated aqueous NaHCO3, and brine
successfully. The organic layer was concentrated to give a white
powder (1.73 g, 95%) as a mixture of 16 and 15 in a ratio of 2:1.
AGI-7 (5). The vinylogous amide ester 13 (165 mg, 0.36 mmol)
was refluxed in 70% aqueous formic acid (15 mL) for 1 day. After
reaction, mixture was concentrated under reduced pressure, and
the resulting residue was treated with EtOAc and washed with
saturated aqueous NaHCO3 two times and brine once. The
separated organic layer was dried over anhydrous Na2SO4 and
evaporated under reduced pressure to give a white powder. To
the above crude product in acetone (15 mL) cooled in ice bath
was added freshly prepared J ones reagent (2 mL; 0.56 g of
chromium trioxide in 0.9 mL of sulfuric acid and 2.4 mL of water)
dropwise. It was stirred at 0 °C for 30 min and then at room
temperature for 30 min. Water (30 mL) was added, and the
mixture was stirred for another 10 min. The reaction mixture
was then neutralized with saturated aqueous NaHCO3, satu-
rated with NaCl, and extracted with EtOAc four times. The
combined organic extracts were washed with brine once, dried
over anhydrous Na2SO4, and evaporated under reduced pressure.
The resulting residue was further purified by column chroma-
tography (hexanes/acetone ) 2:1) to give 45 mg (56%) of pure
AGI-7 as a white solid: Rf ) 0.25 (hexanes/acetone ) 2:1); mp
1
240 °C dec; H NMR (acetone-d6, 300 MHz) δ 2.53 (s, 3H), 6.49
2,4-Bis-ben zyloxy-6-(2-oxop r op yl)ben zoic Acid (11). Py-
ridine (447 µL) was added to a stirred mixture of 10 (900 mg,
2.29 mmol) in acetic anhydride (2.5 mL) under argon. The solid
was dissolved instantly. After 2 min, it gave rise to a precipitate
and solidified. Dry Et2O (20 mL) was added to facilitate the
stirring. The solid was filtered and washed with Et2O after being
stirred overnight. The obtained solid was suspended in water
(d, J ) 2.4 Hz, 1H), 7.72 (d, J ) 2.4 Hz, 1H), 8.47 (s, 1H), 9.81
(br s, 1H), 11.0 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ 196.4,
166.4, 163.7, 163.3, 155.2, 135.1, 116.9, 104.1, 102.7, 98.5, 28.5;
IR (KBr) νmax 3422, 3188, 1685, 1651, 1165 cm-1; HRMS calcd
for C11H8O5 (M+) 220.0372, found 220.0379. Anal. Calcd for
C
11H8O5: C, 60.00; H, 3.66. Found: C, 60.35; H, 3.76.
Sesca n d elin (4). Ra cem ic Red u ction . To a solution of
AGI-7 (5) (33 mg, 0.15 mmol) and cerium chloride heptahydrate
(170 mg, 0.45 mmol) in MeOH (10 mL) was added sodium
borohydride (17 mg, 0.45 mmol). The mixture was stirred at
room temperature for 10 minutes, and then the reaction was
quenched with acetone. The solvent was evaporated, and the
(19) The enantiomeric excess of 4 was determined by chiral station-
ary phase HPLC analysis after transformation to the known triacetyl
derivative9 (CHIRALPAK AD-H, hexane/2-propanol (4: 1, v/v), flow
rate 1.0 mL/min, retention time 8.12 min (+)-isomer and 8.85 min (-)-
isomer, detected at 254 nm).

3130 J . Org. Chem., Vol. 67, No. 9, 2002
Notes
residue was diluted with CH2Cl2. The organic layer was washed
with 0.5 N aqueous HCl and brine, dried (MgSO4), and concen-
trated. After purification by short column chromatography
(hexanes/acetone ) 1:1), 31 mg of racemic sescandelin was
obtained as a white solid in 96% yield.
J ) 2.1 Hz, 1H), 4.95 (m, 1H), 4.39 (d, J ) 4.5 Hz, 1H, OH),
1.50 (d, J ) 6.6 Hz, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 165.7,
165.5, 163.5, 141.7, 137.6, 122.2, 102.0, 101.8, 98.9, 63.3, 23.3;
IR (KBr) νmax 3451, 3135, 1688, 1650, 1622, 1520 cm-1; HRMS
calcd for C11H10O5 (M+) 222.0528, found 222.0525. Anal. Calcd
for C11H10O5: C, 59.46; H, 4.54. Found: C, 59.71; H, 4.74.
En a n tioselective Red u ction : AGI-7 (5) (35 mg, 0.16 mmol)
in THF (10 mL) was treated with (S)-oxazaborolidine reagent18
(1-bu t yl-3,3-diph en ylt et r a h ydr opyr r olo[1,2-c][1,3,2]oxa za -
borole, 60 µL, 0.5 M solution in THF) and borane-methyl sulfide
complex (80 µL, 0.16 mmol) at -78 °C, and stirring was con-
tinued for 19 h at this temperature. The reaction was quenched
with water, diluted with EtOAc, and then washed with 1 N
aqueous HCl to remove the pyrrolidine. The organic layer was
dried over anhydrous Na2SO4 and evaporated. The residue was
applied to column chromatography (hexanes/acetone ) 1:1) to
Ack n ow led gm en t. This work was supported by
Grant No. 1999-2-21500-001-3 from the Basic Research
Program of the Korea Science & Engineering Founda-
tion.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
1
NMR spectra of compounds 9, 10, 11, 13, 5, and 4; H NMR
spectra of the methyl ester of 11 as well as crude 12, 14, and
a mixture of 5 and 17 from eq 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
furnish 32 mg of sescandelin as a white solid in 88% yield: [R]21
D
) +31.6 (c 0.02, MeOH); Rf ) 0.39 (hexanes/acetone ) 3:4); mp
187-188 °C; 1H NMR (acetone-d6, 300 MHz) δ 11.47 (s, 1H, OH),
9.64 (s, 1H, OH), 7.42 (s, 1H), 6.74 (d, J ) 2.1 Hz, 1H), 6.45 (d,
J O010789B