First syntheses of (-)-tauranin and antibiotic (-)-BE-40644 based on lipase-catalyzed optical resolution of albicanol

Article abstract of DOI:10.1248/cpb.57.1103

First syntheses of sesquiterpene quinones (-)-tauranin and (-)-BE-40644 which exhibited strong cytotoxicity against several cancer cell lines, were achieved from (8aS)-albicanol obtained by enzymatic optical resolution. By comparison of the sign of specif

Full text of DOI:10.1248/cpb.57.1103

October 2009
Chem. Pharm. Bull. 57(10) 1103—1106 (2009)
1103
ꢀ
ꢀ
First Syntheses of ( )-Tauranin and Antibiotic ( )-BE-40644 Based on
Lipase-Catalyzed Optical Resolution of Albicanol
Sadayuki ISHII, Mikio FUJII,* and Hiroyuki AKITA*
Faculty of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 247–8510, Japan.
Received June 23, 2009; accepted July 14, 2009; published online July 15, 2009
First syntheses of sesquiterpene quinones (ꢀ)-tauranin and (ꢀ)-BE-40644 which exhibited strong cytotoxic-
ity against several cancer cell lines, were achieved from (8aS)-albicanol obtained by enzymatic optical resolution.
By comparison of the sign of specific rotation between synthetic (12bS)-BE-40644 and natural (ꢀ)-BE-40644, the
absolute configurations of natural (ꢀ)-BE-40644 were determined to be 4aS, 6aS, 12aR, 12bS.
Key words tauranin; BE-40644; sesquiterpene quinone; albicanol; lipase; regioselective acetylation
A sesquiterpene quinone (ꢀ)-tauranin (1) (Fig. 1) was iso- lowed by lipase-catalyzed resolution again to afford (8aS)-5.
lated from mold Oospora aurantia1,2) and fungus Phyllosticta Thus obtained (8aS)-5 was deacylated to afford (8aS)-4 in
spinarum,3) and the absolute configurations of (ꢀ)-1 was de- 70% overall yield (3 steps) with ꢁ99% ee. This procedure
termined by Kawashima et al.1) It has been reported to pos- was an easy and effective method to prepare large amount of
sess apoptotic activity toward several human solid tumor cell both enantiomers of optically active albicanol since the enzy-
lines,3) and inhibitory activity against the incorporation of matic optical resolution of rac-4 was performed on 10 g scale
acetate-1-14C into cholesterol.4) Meanwhile sesquiterpene of rac-4 affording 4.3 g of (8aR)-4 and 3.7 g of (8aS)-4.
quinone BE-40644 ((ꢀ)-2) (Chart 1), structurally similar to While several synthetic methods of optically active 4 were
(ꢀ)-1, was isolated from Actinoplanes sp. A 40644.5) It has reported,14,15) our methods were considered to be one of prac-
been reported to inhibit the thioredoxin (TRX) system and to tical methods to access both enantiomers of optically active
exhibit cytotoxicity against several human tumor cell lines.5—7) 4.
In addition, strong repression of human immunodeficiency
Herein we report the first syntheses of (8aS)-1 and (12bS)-
virus (HIV) virus replication was also reported for this com- 2 from (8aS)-4 possessing apparent stereochemistry and the
pound.7) In spite of its interesting biological activities, the ab- determination of the absolute structure of (ꢀ)-2 based on the
solute configurations of (ꢀ)-2 have not been determined, chiral synthesis of (12bS)-2.
while racemic synthesis of an epimer (rac-3) at C(6a) of 2
was reported.8) At the same time, (ꢀ)-2 has recently become Results and Discussion
an attractive subject for biochemists due to its unusual
Synthesis of (8aS)-Tauranin (1) Common aromatic
biosynthetic pathway.9—12) Determination of the absolute building block 6 for the syntheses of (8aS)-1 and (8aS)-2 was
configuration could provide useful information on its medici- prepared from methyl 3,5-dihydroxybenzoate by reported
nal purpose as well as biosynthetic study.
procedure.16) Dess–Martin oxidation of (8aS)-4 in the pres-
On the other hand, we developed the lipase-catalyzed opti- ence of NaHCO3 gave (8aS)-albicanal (7) in 94% yield,
cal resolution of racemic albicanol (rac-4).13) Thus, rac-4 which was reacted with an anion generated from 6 by treat-
was treated with vinyl myristate in the presence of lipase QL ment with n-BuLi to afford a diastereomeric mixture of
to give (8aR)-4 (43%, 99% ee) and (8aS)-5 (57%, 82% ee) as (8aS)-8 in 91% yield as shown in Chart 2. The diastere-
shown in Chart 1. In order to enrich the enantiomeric purity omeric mixture of (8aS)-8 was converted to (8aS)-9 by Bar-
of (8aS)-5 with 82% ee, obtained (8aS)-5 was deacylated fol- ton McCombie’s method17—19) in 76% overall yield. Several
conditions were tested for deprotection of the methoxy
methyl (MOM) group of (8aS)-9, since the removal of MOM
was accompanied with cyclization by attacking of the result-
ing phenolic oxygen at C(2) carbon and afforded undesired
products.20) Acidic conditions using camphor sulfonic acid
(CSA) for the deprotection of (8aS)-9 were investigated to af-
ford (8aS)-10 and (8aS)-11 effectively as shown in Table 1. It
was found that distribution of deprotected products was gov-
erned by the concentration of CSA used in EtOH. CSA
Fig. 1. Structures of (ꢀ)-Tauranin (1), (ꢀ)-BE-40644 (2) and rac-3
Chart 1
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: mfujii@phar.toho-u.ac.jp; akita@phar.toho-u.ac.jp

1104
Vol. 57, No. 10
(9 mM)-assisted deprotection of (8aS)-9 first gave (8aS)-12 in ꢀ47.9 (cꢂ0.28, MeOH)} of synthetic (8aS)-1 were identical
91% yield (Table 1, entry 1). The use of CSA (19 to 35 mM) with those {[a]D21 ꢀ148 (cꢂ0.10, MeOH)}1) of the natural
afforded (8aS)-10 with one MOM group and fully depro- (8aS)-1. Overall yield of (8aS)-1 from (8aS)-4 was found to
tected (8aS)-11 (entries 2, 3). The use of 100 mM CSA (entry be 31% in 6 steps.
4) was found to be the best condition for deprotection of
Synthesis of (12bS)-BE-40644 (2) Next synthesis of
(8aS)-9 to afford (8aS)-10 (42% yield) and (8aS)-12 (52% (12bS)-2 was achieved from (8aS)-10 (Chart 3). Selective de-
yield), while treatment with a higher CSA concentration protection of (8aS)-9 under 100 mM CSA condition for 3 d
(entry 5, 140 mM) decreased the total yield of (8aS)-10 and gave (8aS)-10 in 42% yield. Regioselective acetylation with
(8aS)-11 due to the undesired cyclization. For preparation of vinyl acetate catalyzed by lipase PS-C to afford (8aS)-13 in
(8aS)-11, (8aS)-9 was treated with 100 mM of CSA for 3.5 d 92% yield. This enzymatic procedure proceeded under mild
to afford (8aS)-10 in 18% and (8aS)-11 in 62% yield.
conditions to afford selectively monoacetylated product
Furthermore, (8aS)-10 was again treated with 100 mM of (8aS)-13 with benzyl alcohol moiety, while chemical acetyla-
CSA to give (8aS)-11 in 70% yield. Finally, oxidation of tion using acetic anhydride and pyridine afforded (8aS)-13
(8aS)-11 by Fremy’s salt ((KSO3)2NO) in phosphate buffer together with diacetate of (8aS)-10. Treatment of (8aS)-13
(pH 7.2) gave (8aS)-1 in 63% yield.8,21) Spectral data includ- with N-(phenylseleno)phthalimide22,23) afforded a diastere-
ing H-, 13C-NMR, IR, MS and specific rotation {[a]D23 omeric mixture of phenylselenide derivatives, whose phenylse-
1
lenyl group was removed by tributyltinhydride in the pres-
ence of 2,2ꢃ-azobis iso butyronitrile (AIBN) to afford
(12bS)-14 as a diastereomeric mixture (6aS : 6aRꢂ11 : 1) in
82% yield (2 steps). Treatment of (12bS)-14 with CSA fol-
lowed by silica gel column chromatographic separation af-
forded (12bS)-15 as a single isomer in 86% yield. It was
treated with Fremy’s salt in phosphate buffer (pH 7.2) to give
Table 1. Effect of CSA Concentration on Deprotection of (8aS)-9
1
(12bS)-2 in 43% yield. Spectral data including H-, 13C-
Conc. of CSA Time
(8aS)-12
(%)
(8aS)-10
(%)
(8aS)-11
NMR, IR, MS and specific rotation of synthetic (12bS)-2
{[a]D20 ꢀ50.7 (cꢂ0.20, MeOH)} were identical with those
{[a]D21 ꢀ48.5 (cꢂ0.887, MeOH)}5) of natural (ꢀ)-2. By
comparison of the sign of specific rotation between synthetic
(12bS)-2 and natural (ꢀ)-2, the absolute structure of natural
(ꢀ)-2 was determined to be 4aS, 6aS, 12aR, 12bS.
Entry
(mM)
(d)
(%)
a)
a)
1
2
3
4
5
9
19
35
100
140
7
7
5
3
2
91
29
14
—
—
24
31
42
30
16
32
52
49
a)
—
a)
—
Conditions: (8aS)-9; 15 mmol, EtOH; 1 ml, at 20 °C. a) Not isolated.
Chart 2
Chart 3

October 2009
1105
Conclusion
10 (from fractions eluted by Hex : AcOEtꢂ5 : 1) and (8aS)-11 (from frac-
tions eluted by Hex : AcOEtꢂ2 : 1). 1-{[(1S,4aS,8aS)-Decahydro-2-methyl-
ene-5,5,8a-trimethylnaphthalen-1-yl]methyl}-4-hydroxymethyl-2,6-
First syntheses of sesquiterpene quinones, (8aS)-tauranin
(1) and (12bS)-BE-40646 (2) were achieved in this study.
Overall yields of (8aS)-1 and (12bS)-2 were 31% in 6 steps
and in 7.6% in 10 steps from (8aS)-4, respectively. By com-
parison of the sign of specific rotation between synthetic
(12bS)-2 and natural (ꢀ)-2, the absolute configurations of
natural (ꢀ)-2 were determined to be 4aS, 6aS, 12aR, 12bS.
1
bis(methoxymethyloxy)benzene (8aS)-12: H-NMR (CDCl3) d: 0.83 (6H, s),
0.87 (3H, s), 1.12—1.75 (9H, m), 1.85—1.93 (2H, m), 2.26—2.38 (1H, m),
2.53—2.59 (1H, m), 2.75 (1H, dd, Jꢂ13.8, 3.6 Hz), 2.88 (1H, dd, Jꢂ13.8,
9.4 Hz), 3.49 (6H, s), 4.59 (2H, s), 4.68 (1H, s), 4.99 (1H, s), 5.18 (2H,
d, Jꢂ6.8 Hz), 5.20 (2H, d, Jꢂ6.8 Hz), 6.75 (2H, s). 13C-NMR (CDCl3) d:
14.2, 19.5, 19.5, 21.7, 24.6, 33.6, 33.7, 38.6, 38.8, 40.4, 42.4, 55.2, 56.0,
56.2 (2C), 65.4, 94.5 (2C), 106.3, 106.4 (2C), 120.0, 139.7, 149.6, 156.2 (2C).
IR (neat) cmꢀ1: 3323, 1586, 1154, 1045. HR-EI-MS m/z: 432.2880 (Calcd
for C26H40O5: 432.2876). 1-{[(1S,4aS,8aS)-Decahydro-2-methylene-5,5,8a
trimethylnaphthalen-1-yl]methyl}-6-hydroxy-4-hydroxymethyl-2-
(methoxymethyloxy)benzene (8aS)-10: 1H-NMR (CDCl3) d: 0.82 (6H, s),
0.86 (3H, s), 1.12—1.49 (7H, m), 1.55—1.75 (2H, m), 1.94—2.00 (2H, m),
2.32—2.43 (2H, m), 2.74 (1H, dd, Jꢂ14.6, 8.6 Hz), 2.85 (1H, dd, Jꢂ14.6,
3.6 Hz), 3.49 (3H, s), 4.55 (2H, br), 4.79 (1H, s), 5.05 (1H, s), 5.17 (1H, d,
Jꢂ6.8 Hz), 5.19 (1H, d, Jꢂ6.8 Hz), 5.30 (1H, s), 6.47 (1H, s), 6.64 (1H, s).
13C-NMR (CDCl3) d: 14.1, 18.9, 19.5, 21.7, 24.6, 33.6, 33.6, 38.6, 38.6,
40.6, 42.2, 55.7, 55.8, 56.2, 65.2, 94.6, 105.0, 106.5, 108.0, 117.5, 139.8,
150.5, 155.1, 156.2. [a]D17 ꢀ14.6 (cꢂ1.23, CHCl3). IR (neat) cmꢀ1: 3366,
1644, 1616, 1592, 1194, 1044. HR-EI-MS m/z: 388.2631 (Calcd for C24H36
O4: 388.2614). 1-{[(1S,4aS,8aS)-Decahydro-2-methylene-5,5,8a-trimethyl-
naphthalen-1-yl]methyl}-2,6-dihydroxy-4-(hydroxymethyl)benzene (8aS)-
11: 1H-NMR (CDCl3) d: 0.81 (3H, s), 0.82 (3H, s), 0.86 (3H, s), 1.13—1.21
(3H, m), 1.30—1.41 (2H, m), 1.46—1.64 (3H, m), 1.70—1.78 (1H, m),
1.97—2.06 (2H, m), 2.28—2.33 (1H, m), 2.39 (1H, ddd, Jꢂ12.0, 4.0,
2.8 Hz), 2.68 (1H, dd, Jꢂ14.8, 8.4 Hz), 2.87 (1H, dd, Jꢂ14.8, 3.4 Hz), 4.53
(2H, s), 4.87 (1H, s), 5.04 (2H, s), 5.08 (1H, s), 6.36 (2H, s). 13C-NMR
(CDCl3) d: 14.1, 18.6, 19.5, 21.7, 24.6, 33.6, 33.6, 38.6, 38.6, 40.7, 42.2,
55.6, 55.8, 64.9, 106.6, 106.8 (2C), 115.4, 139.5, 150.9, 155.1 (2C). [a]D18
ꢀ51.0 (cꢂ0.415, MeOH). IR (neat) cmꢀ1: 3360, 2927, 1621, 1595, 1199,
1034. HR-EI-MS m/z: 344.2357 (Calcd for C22H32O3: 344.235).
Experimental
General All melting points were measured on a Yanaco MP-3S melt-
ing point apparatus and are uncorrected. 1H- (400 MHz) and 13C-NMR
(100 MHz) spectra were recorded on JEOL AL-400 spectrometer in CDCl3.
High-resolution mass spectra (HRMS) were obtained with a JEOL JMS-AM
II 50. IR spectra (ATR method) were recorded with a JASCO FT/IR 4100
spectrometer. Optical rotations were measured with a JASCO DIP-370 digi-
tal polarimeter. For silica gel column chromatography, Kieselgel 60 and
silica gel 60N (spherical and neutral type) were used. Chemicals were pur-
chased from Tokyo Kasei Industry Co., Ltd., Wako Chemicals or Aldrich
Inc. otherwise indicated.
Synthesis of (8aS)-1 Albicanal ((8aS)-7) To a mixture of (8aS)-4
(350 mg, 1.57 mmol, ꢁ99% ee) and NaHCO3 (2.25 g, 26.8 mmol) in CH2Cl2
was added DMP (1.14 g, 2.69 mmol) at 0 °C and the resulting mixture was
stirred for 2 h at 0 °C. After filtration of the mixture, the filtrate was evapo-
rated under reduced pressure. The residue was purified by silica gel chro-
matography (Hex : AcOEtꢂ200 : 1) to give (8aS)-7 (326 mg, 1.48 mmol,
94%). (8aS)-7 was used rapidly for the next reaction to avoid epimerization
at 1-position.
1-{[(1S,4aS,8aS)-Decahydro-2-methylene-5,5,8a-trimethylnaphthalen-
1-yl]methyl}-4-[(t-butyldimethylsilyl)oxymethyl]-2,6-di(methoxymethyl-
oxy)benzene ((8aS)-9) To a solution of 6 (2.56 g, 7.47 mmol) in dry THF
(20 ml) was added n-BuLi (2.6 M hexane solution, 2.4 ml) at room tempera-
ture (rt) under argon atmosphere and the resulting mixture was stirred for
1 h. Then a solution of (8aS)-7 (471 mg, 2.14 mmol) in dry THF (10 ml) was
added to the mixture and stirred for further 3 h at rt. The reaction mixture
was poured into ice-cooled aq. NH4Cl solution and extracted by Et2O twice.
The organic layers were combined, dried over Na2SO4 and evaporated under
reduced pressure. The residue was purified by silica gel chromatography
(silica gel: 50 g, Hex : AcOEtꢂ50 : 1) to give a diastereomeric mixture
(1 : 1.2) of (8aS)-8 (1.09 g, 1.93 mmol, 91%). To the solution of the dais-
teromeric mixture of (8aS)-8 (1.09 g, 1.93 mmol) in dry THF (20 ml) was
added NaHMDS (1 M THF solution, 9.75 ml) at ꢀ78 °C and the resulting
mixture was stirred for 0.5 h. Then CS2 (2.33 ml, 38.6 mmol) was added to
the mixture, the mixture was stirred for 1 h until the temperature of the mix-
ture was warmed up to ꢀ65 °C. Then CH3I was added to the mixture, the re-
sulting mixture was stirred for 1 h, poured into aq. Na2S2O3 and extracted by
AcOEt twice. The organic layers were combined, dried over Na2SO4 and
evaporated under reduced pressure. The residue was purified by silica gel
chromatography (silica gel: 20 g, Hex : AcOEtꢂ200 : 1) to afford a diastere-
omeric mixture of methyl dithiocarbonate of (8aS)-8 (1.17 g, 1.79 mmol,
93%). A solution of the methyl dithiocarbonate of (8aS)-8 (1.98 g, 3.03
mmol), AIBN (252 mg, 1.53 mmol) and SnBu3H (4.00 ml, 15.3 mmol) in
benzene was refluxed for 5 h under Ar atmosphere. The mixture was cooled
to rt and evaporated under reduced pressure. The residue was purified by sil-
ica gel chromatography (silica gel: 70 g, Hex : AcOEtꢂ300 : 1) to afford
Preparation of (8aS)-11 To a solution of (8aS)-9 (0.104 g, 0.190 mmol)
in EtOH (10 ml) was added CSA (0.268 g, 1.15 mmol) and the resulting mix-
ture was stirred at 20 °C for 3 d. The reaction was quenched by addition of
sat. aq. NaHCO3 and the resulting mixture was extracted by CH2Cl2 and
evaporated under reduced pressure. The residue was purified by silica gel chro-
matography to afford (8aS)-10 (from fractions eluted by Hex : AcOEtꢂ5 : 1,
13.1 mg, 0.034 mmol, 18%) and (8aS)-11 (from fractions eluted by
Hex : AcOEtꢂ2 : 1, 40.2 mg, 0.117 mmol, 62%). The recovered (8aS)-10
(31.0 mg, 0.080 mmol) in EtOH (5 ml) was treated with CSA (107 mg,
0.463 mmol) for 3 d to afford (8aS)-11 (19.3 mg, 0.056 mmol, 70%).
(ꢀ)-Tauranin ((8aS)-1) To a solution of (8aS)-11 (10.0 mg, 0.029 mmol)
in acetone (10 ml) was added (KSO3)2NO (38.9 mg, 60—75% purity) in
phosphate buffer (3 ml, pH 7.2) at 0 °C and the resulting mixture was stirred
at rt for 6.5 h. The reaction was quenched by addition of sat. aq. NaHCO3
and the resulting mixture was extracted by Et2O and evaporated under re-
duced pressure. The residue was purified by silica gel chromatography (Sil-
ica gel 60N (spherical and neutral type, purchased from Kanto Chemical
Co., Inc.): 2.5 g, Hex : AcOEtꢂ6 : 1} to afford (8aS)-1 (6.5 mg, 0.018 mmol,
63%). Yellowish powder. mp 149—150 °C (decompose) (lit1), mp 153 °C
(decompose)). 1H-NMR (CDCl3) d: 0.77 (3H, s), 0.82 (3H, s), 0.87 (3H, s),
1.15—1.41 (5H, m), 1.53—1.62 (2H, m), 1.69—1.73 (1H, m), 1.77 (1H,
br d, Jꢂ12.4 Hz), 1.90—1.97 (2H, m), 2.28—2.32 (1H, m), 2.41 (1H, br d,
Jꢂ10.8 Hz), 2.55 (1H, dd, Jꢂ13.8, 3.0 Hz), 2.66 (1H, dd, Jꢂ13.8, 10.8 Hz),
4.54 (2H, s), 4.67 (2H, s), 6.66 (1H, s), 6.95 (1H, s). 13C-NMR (CDCl3) d:
14.0, 19.1, 19.5, 21.7, 24.5, 33.6, 33.6, 38.3, 38.8, 40.2, 42.1, 54.4, 55.5,
58.9, 106.6, 122.4, 133.9, 142.3, 148.9, 151.0, 183.2, 187.6. [a]D23 ꢀ147.9
(cꢂ0.28, MeOH), lit1) [a]D21 ꢀ148 (cꢂ0.10, MeOH). IR (neat) cmꢀ1: 3490,
3338, 2927, 1660, 1640, 1619, 1191. HR-EI-MS m/z: 358.2149 (Calcd for
C22H30O4: 358.2144).
1
(8aS)-9 (1.35 g, 2.47 mmol, 82%). H-NMR (CDCl3) d: 0.08 (6H, s), 0.83
(6H, s), 0.87 (3H, s), 0.93 (9H, s), 1.08—1.50 (6H, m), 1.53—1.72 (2H, m),
1.86—1.94 (2H, m), 2.29 (1H, ddd, Jꢂ12.6, 4.4, 2.4 Hz), 2.56 (1H, Jꢂ9.2,
3.2 Hz), 2.74 (1H, dd, Jꢂ13.8, 3.8 Hz), 2.86 (1H, dd, Jꢂ13.8, 9.2 Hz), 3.49
(6H, s), 4.65 (2H, s), 4.68 (1H, s), 4.99 (1H, s), 5.16 (2H, d, Jꢂ6.4 Hz), 5.18
(2H, d, Jꢂ6.4 Hz), 6.73 (2H, s). 13C-NMR (CDCl3) d: ꢀ5.28 (2C), 14.2,
18.4, 19.5, 21.8, 24.6, 25.9 (3C), 33.6, 33.7, 38.6, 38.8, 40.4, 42.4, 55.2,
55.9, 56.1 (2C), 64.9, 94.6 (2C), 105.6 (2C), 106.3, 119.2, 140.3, 149.7,
156.0 (2C). [a]D15 ꢀ18.0 (cꢂ1.02, CHCl3). IR (neat) cmꢀ1: 2929, 1586,
1153, 1101, 926. HR-EI-MS m/z: 546.3742 (Calcd for C32H54O5Si
546.3741).
Synthesis of (12bS)-2. 4-Acetoxymethy-1-{[(1S,4aS,8aS)-decahydro-2-
methylene-5,5,8a-trimethylnaphthalen-1-yl]methyl}-2-hydroxy-6-
(methoxymethyloxy)benzene ((8aS)-13) (8aS)-10 (106 mg, 0.273 mmol,
42%) was prepared from (8aS)-9 (355 mg, 0.650 mmol) by the method de-
scribed above. To a solution of (8aS)-10 (106 mg, 0.273 mmol) and vinyl ac-
etate (0.05 ml, 0.546 mmol) in i-Pr2O (10 ml) was added lipase PS-C (22 mg)
and the resulting mixture was stirred at 40 °C for 9 h. The mixture was fil-
trated by Celite 545 and evaporated under reduced pressure. The residue was
purified by silica gel chromatography (silica gel: 10 g, Hex : AcOEtꢂ15 : 1)
General Methods for Removal of MOM Group (Table 1) To a solu-
tion of (8aS)-9 (8.0 mg, 0.015 mmol) in EtOH (1 ml) was added various
amount of CSA as shown in Table 1 and the resulting mixture was stirred
at 20 °C. The reaction was quenched by addition of sat. aq. NaHCO3 and
the resulting mixture was extracted by CH2Cl2 and evaporated under
reduced pressure. The residue was purified by silica gel chromatography to
afford (8aS)-12 (from fractions eluted by Hex : AcOEtꢂ10 : 1), (8aS)-
1
to afford (8aS)-13 (109 mg, 0.253 mmol, 92%). H-NMR (CDCl3) d: 0.82
(3H, s), 0.82 (3H, s), 0.86 (3H, s), 0.88—0.94 (1H, m), 1.15—1.50 (5H, m),
1.54—1.63 (1H, m), 1.71—1.75 (1H, m), 1.90—1.99 (2H, m), 2.09 (3H, s),

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Vol. 57, No. 10
(CDCl3) d: 0.72 (3H, s), 0.81 (3H, s), 0.89 (3H, s), 0.84—0.92 (2H, m), 1.14
(1H, dt, Jꢂ13.4, 4.4 Hz), 1.19 (3H, s), 1.39—1.46 (3H, m), 1.52—1.61 (4H,
m), 1.81 (1H, brd, Jꢂ12.6 Hz), 2.09 (1H, br), 2.32—2.41 (2H, m), 2.60 (1H,
d, Jꢂ20.4 Hz), 4.52 (2H, s), 6.64 (1H, s). 13C-NMR (CDCl3) d: 13.8, 16.7,
18.1, 18.3, 21.9, 27.2, 33.2, 33.7, 38.5, 39.7, 39.9, 41.6, 48.4, 55.1, 59.6, 79.8,
120.0, 131.7, 144.1, 153.6, 182.1, 186.7. [a]D20 ꢀ50.7 (cꢂ0.20, MeOH), lit5)
[a]D21 ꢀ48.5 (cꢂ0.887, MeOH). IR (neat) cmꢀ1: 3444, 2925, 1651, 1609,
1250, 1184. HR-EI-MS m/z: 358.2133 (Calcd for C22H30O4: 358.2144).
2.30—2.43 (2H, m), 2.75 (1H, dd, Jꢂ14.6, 8.6 Hz), 2.84 (1H, dd, Jꢂ14.6,
3.4 Hz), 3.50 (3H, s), 4.79 (1H, s), 4.97 (2H, s), 5.05 (1H, s), 5.17 (1H, d,
Jꢂ6.6 Hz), 5.20 (1H, d, Jꢂ6.6 Hz), 5.40 (1H, s), 6.45 (1H, s), 6.64 (1H, s).
13C-NMR (CDCl3) d: 14.1, 14.1, 19.0, 19.5, 21.0, 21.7, 24.6, 33.6, 33.6,
38.6, 38.6, 40.6, 42.2 , 55.7, 56.2, 66.2, 94.7, 106.4, 106.5, 109.4, 118.3,
134.5, 150.4, 155.0, 156.2, 171.1. [a]D23 ꢀ10.3 (cꢂ0.37, CHCl3). IR (neat)
cmꢀ1: 3417, 1738, 1624, 1595, 1153, 1050. HR-EI-MS m/z: 430.2713
(Calcd for C26H38O5: 430.2719).
(4aS,6aS,12aR,12bS)-9-Acetoxymethyl-1,2,3,4,4a,5,6,6a,12a,12b-deca-
hydro-11-methoxymethyloxy-4,4,6a,12b-tetramethyl-benzo[a]xanthene
((12bS)-14) To a solution of N-(phenylseleno)phthalimide (65.8 mg, 0.218
mmol) and SnCl4 (0.023 ml, 0.200 mmol) in dry CH2Cl2 (8 ml) was added
(8aS)-13 (77.4 mg, 0.180 mmol) dissolved in dry CH2Cl2 (6 ml) at ꢀ78 °C
and the resulting mixture was stirred for 2 h at the same temperature. The
mixture was quenched by addition of sat. aq. NaHCO3 and extracted by
CH2Cl2 twice. The CH2Cl2 layers were combined, dried over Na2SO4 and
evaporated under reduced pressure. The residue was purified by silica gel
chromatography (silica gel: 20 g, Hex : AcOEtꢂ30 : 1) to afford a diastere-
omeric mixture of a phenylselenide derivative (86.7 mg, 0.148 mmol, 82%).
A solution of the phenylselenide derivative (104 mg, 0.178 mmol), AIBN
(6.3 mg, 0.038 mmol) and SnBu3H (0.115 ml, 0.493 mmol) in benzene (5 ml)
was refluxed for 1.5 h under argon atmosphere. The mixture was cooled to rt
and evaporated under reduced pressure. The ratio of the diastereomeric mix-
ture of (12bS)-14 was determined by measurement of 1H-NMR spectra
(6aS:6aRꢂ11 : 1). The residue was purified by silica gel chromatography
(silica gel: 5 g, Hex : AcOEtꢂ300 : 1) to afford a diastereomeric mixture
References and Notes
1) Kawashima K., Nakanishi K., Tada M., Tetrahedron Lett., 5, 1227—
1231 (1964).
2) Kawashima K., Nakanishi K., Nishikawa H., Chem. Pharm. Bull., 12,
796—803 (1964).
3) Kithsiri W. E. M., Priyani A. P., Marilyn T. M., Malkanthi K. G., Eliza-
beth A. A., Leslie G. A. A., J. Nat. Prod., 71, 218—222 (2008).
4) Ozawa H., Ichikawa H., Yakugaku Zasshi, 90, 480—485 (1970).
5) Torigoe K., Wakasugi N., Sakaizumi N., Ikejima T., Suzuki H., Kojiri
K., Suda H., J. Antibiot., 49, 314—317 (1996).
6) Koyanagi H., Wakasugi N., Yoshimatsu K., Takashima Y., Yodoi J.,
Momoi M., Suda T., Kasahara T., Yamaguchi Y., Biochem. Biophys.
Res. Commun., 213, 1140—1147 (1995).
7) Torigoe K., Wakasugi N., Sakaizumi N., Suzuki H., Kojiri K., Suda H.,
Jpn. Patent, JPO 07304762, A 19951121 (1995).
8) Tsujimori H., Mori K., Biosci. Biotechnol. Boichem., 65, 167—171
(2001).
9) Kawasaki T., Kuzuyama T., Furuhata K., Itoh N., Seto, H., Dairi T., J.
Antibiot., 56, 957—966 (2003).
10) Kawasaki T., Kuzuyama T., Kuwamori Y., Matsuura N., Itoh N., Fu-
ruhata K., Seto H., Dairi T., J. Antibiot., 57, 739—747 (2004).
11) Dairi T., J. Antibiot., 58, 227—243 (2005).
12) Wu X., Flatt P. M., Schlorke O., Zeeck A., Dairi T., Mahmud T.,
ChemBioChem, 8, 239—248 (2007).
13) Fujii M., Ishii S., Akita H., J. Mol. Cat. B; Enzymatic, 59, 254—260
(2009).
14) Poigny S., Huor T., Guyot M., Samadi M., J. Org. Chem., 64, 9318—
9320 (1999).
15) Furuichi N., Hata T., Seotjipto H., Kato M., Katsumura S., Tetrahe-
dron, 57, 8425—8442 (2001).
16) Treadwell E. W., Cermak S. C., Wiemer D. F., J. Org. Chem., 64,
8718—8723 (1999).
17) Barton D. H., McCombie S. W., J. Chem. Soc., Perkin Trans. 1, 1975
1574—1785 (1975).
1
(11 : 1) of (12bS)-14 (76.0 mg, 0.176 mmol, 99%). H-NMR for major iso-
mer of (12bS)-14 (CDCl3) d: 6.45, 6.55. 1H-NMR for minor isomer of
(12bS)-14 (CDCl3) d: 6.47, 6.57. IR (neat) cmꢀ1: 2925, 1740, 1618, 1586,
1157, 1058. HR-EI-MS m/z: 430.2620 (Calcd for C26H38O5: 430.2719).
(4aS,6aS,12aR,12bS)-1,2,3,4,4a,5,6,6a,12a,12b-Decahydro-11-hy-
droxy-9-hydroxymethyl-4,4,6a,12b-tetramethyl-benzo[a]xanthene
((12bS)-15) To a solution of (12bS)-14 (67.0 mg, 0.156 mmol) in EtOH
(7 ml) was added CSA (113 mg, 0.486 mmol) and the mixture was stirred for
24 h at 40 °C. The mixture was poured into sat. aq. NaHCO3 and extracted
by CH2Cl2 twice. The CH2Cl2 layers were combined, dried over Na2SO4 and
evaporated under reduced pressure. The residue was purified by silica gel
chromatography (silica gel: 20 g, Hex : AcOEtꢂ4 : 1) to afford (12bS)-15
1
(46.5 mg, 0.135 mmol, 87%) as a single isomer. H-NMR (CDCl3) d: 0.69
(3H, s), 0.81 (3H, s), 0.90 (3H, s), 0.85—0.93 (2H, m), 1.16 (3H, s), 1.01—
1.19 (1H, m), 1.37—1.44 (3H, m), 1.48—1.65 (4H, m), 1.79 (1H, br), 1.87
(1H, br d, Jꢂ12.4 Hz), 2.10—2.16 (1H, m), 2.61 (1H, dd, Jꢂ17.6, 8.0 Hz),
2.74 (1H, d, Jꢂ17.6 Hz), 4.53 (2H, s), 5.30 (1H, br), 6.35 (1H, s), 6.38 (1H,
s). 13C-NMR (CDCl3) d: 14.1, 17.2, 18.2, 18.5, 21.9, 27.1, 33.2, 33.7, 38.4,
40.1, 40.6, 41.9, 48.9, 55.3, 65.2, 75.6, 104.9, 108.1, 109.6, 139.4, 153.8,
155.8. [a]D18 ꢀ52.1 (cꢂ0.82, CHCl3). IR (neat) cmꢀ1: 3309, 2925, 1626,
1591, 1517, 1135, 1067. HR-EI-MS m/z: 344.2345 (Calcd for C22H32O3:
344.2351).
18) Katoh T., Nakatani M., Shikita S., Sampe R., Ishiwata A., Ohmori O.,
Nakamura M., Terashima S., Org. Lett., 3, 2701—2704 (2001).
19) Maezawa N., Furuich, N., Tsuchikawa H., Katsumura S., Tetrahedron
Lett., 48, 4865—4867 (2007).
20) Only (6aR)-products8 were obtained, while BE-40644 possessed (6aS)-
configuration.
BE-40644 ((12bS)-2) To a solution of (12bS)-15 (20 mg, 0.058 mmol)
in acetone (6 ml) was added (KSO3)2NO (78 mg, 60—75% purity) in phos-
phate buffer (8 ml, 1 M, pH 7.2) at 0 °C and the resulting mixture was stirred
at rt for 4 h. The reaction was diluted by addition of water and the resulting
mixture was extracted by Et2O and evaporated under reduced pressure. The
residue was purified by silica gel chromatography (silica gel 60N: 1.5 g,
21) Zimmer H., Lankin D. C., Horgan S. W., Chem. Rev., 71, 229—246
(1971).
22) Hori T., Sharpless K. B., J. Org. Chem., 44, 4208—4210 (1979).
23) Barrero A. F., Alvarez-Manzaneda E. J., Chahboun R., Tetrahedron
Lett., 38, 2325—2328 (1997).
1
Hex : AcOEtꢂ10 : 1) to afford (12bS)-2 (9.0 mg, 0.025 mmol, 43%). H-NMR