Total Synthesis of the Antitumor Antibiotic (±)-Fredericamycin A by a Linear Approach

Article abstract of DOI:10.1002/1521-3765(20001103)6:21<3897::AID-CHEM3897>3.0.CO;2-1

A linear approach to the total synthesis of racemic fredericamycin A (1) through the oxidative intramolecular [4 + 2] cycloaddition of a (phenylthio)acetylene - cobalt complex is described, which is applicable for the asymmetric total synthesis of naturally occuring 1. The highlight of this work is the aromatic Pummerer-type reaction with 1-ethoxyvinyl chloroacetate, which effects the introduction of the oxygen functional group to the internal B-ring of the highly functionalized, congested polyaromatic ABC-ring moiety.

Full text of DOI:10.1002/1521-3765(20001103)6:21<3897::AID-CHEM3897>3.0.CO;2-1

FULL PAPER
Total Synthesis of the Antitumor Antibiotic (Æ)-Fredericamycin A
by a Linear Approach
Yasuyuki Kita,* Kiyosei Iio, Ken-ichi Kawaguchi, Nobuhisa Fukuda, Yoshifumi Takeda,
Hiroshi Ueno, Ryuichi Okunaka, Kazuhiro Higuchi, Toshiaki Tsujino,
Hiromichi Fujioka, and Shuji Akai[a]
Abstract: A linear approach to the total synthesis of racemic fredericamycin A (1)
through the oxidative intramolecular [4 ‡ 2] cycloaddition of a (phenylthio)acety-
Keywords: antitumor
cycloadditions ´ fredericamycin A ´
agents
´
lene ± cobalt complex is described, which is applicable for the asymmetric total
synthesis of naturally occuring 1. The highlight of this work is the aromatic
Pummerer-type reaction with 1-ethoxyvinyl chloroacetate, which effects the intro-
duction of the oxygen functional group to the internal B-ring of the highly
functionalized, congested polyaromatic ABC-ring moiety.
Pummerer-type
total synthesis
reactions
´
therefore also its absolute configuration remained unknown.
The majority of the reported approaches feature the con-
struction of the spiro C- or D-ring at their final stages, and the
difficult distinction of the enantioface of the highly sym-
metrical ABC-ring has been the obstacle to their application
to the asymmetric version.
We envisioned that one of the most promising way to the
asymmetric synthesis of 1 would be the preparation of an
intermediate with an optically pure quaternary carbon center
with a definite stereochemistry and the completion of the total
synthesis while retaining its chiral integrity. According to this
strategy, two approaches, that is, a convergent approach via an
intermolecular cycloaddition reaction (Scheme 1a) and a
Introduction
Asymmetric total synthesis of the antitumor antibiotic,
fredericamycin A (1), has been a challenging subject during
these two decades due to its unique structure as well as its
potent antitumor properties (Figure 1).[1] Structurally, 1 con-
sists of two sets of peri-hydroxy tricyclic aromatic moieties
H
O
N
F
OH
O
OH
B
O
A
E
*
C
D
OMe
O
OH
O
a)
Intermolecular
[4+2] cycloaddition
approach
OR
N
F
Figure 1. Fredericamycin A (1).
R
OR
O
O
OR
X
E
O
C
connected through a spiro quaternary carbon center, which is
chiral due to the presence of a single methoxy group at the
most distant position on the A-ring. Intensive efforts toward
this goal include five total syntheses of racemic 1[2±6] and the
first synthesis of optically pure 1 by separation of a fully
protected racemic 1 using a chiral HPLC column;[7] however,
no one has succeeded so far in its asymmetric synthesis and
*
A
D
ref. [8a]
O
OMe
O
OR OR
1
Si
Si
O
O
O
O
O
O
O
b)
A
D * C
A
*
B
D
Intramolecular
[4+2] cycloaddition
approach
OMe
OMe
O
Y
Y
OMe
OMe
[a] Prof. Dr. Y. Kita, Dr. K. Iio, K. Kawaguchi, N. Fukuda, Dr. Y. Takeda,
H. Ueno, Dr. R. Okunaka, K. Higuchi, T. Tsujino, Dr. H. Fujioka,
Dr. S. Akai
Scheme 1. Retrosyntheses of optically active fredericamycin A (1).
Graduate School of Pharmaceutical Sciences
Osaka University, 1-6, Yamadaoka, Suita, Osaka 565-0871 (Japan)
Fax : (‡81) 6-6879-8229
linear approach via an intramolecular cycloaddition reaction
(Scheme 1b), were planned. Only very recently, did we
achieved an asymmetric total synthesis of 1 via a convergent
E-mail: kita@phs.osaka-u.ac.jp
Chem. Eur. J. 2000, 6, No. 21
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Y. Kita et al.
FULL PAPER
approach using a strong base induced intermolecular [4 ‡ 2]
cycloaddition reaction of homophthalic anhydrides.[8, 9] The
regiochemistry of the cycloaddition reaction was controlled
by the phenylsulfinyl substituent (X ˆ PhSO), and thereby the
absolute stereochemistry of natural 1 could be determined for
the first time.
(5 equiv) and a catalytic amount (ca. 0.3 equiv) of p-TsOH in
refluxing toluene[13] exclusively provided 8a (ca. 65% yield).
The use of 7b gave the best yield of the oxygenated product 8
among the four different ethoxyvinyl esters 7a ± d. Note-
worthy, a similar reaction using chloroacetic anhydride
instead of 7b proceeded tardily to give only 6 (ca. 80%
yield). Compound 8a was subjected to successive deprotec-
tion with Bu4NF, BBr3, and 80% aqueous trifluoroacetic acid
to give the ABCD-ring 9 in 62% overall yield from 5a
(Scheme 3). The efficiency of 7b was also apparent from the
similar reaction of 5b, where 8b was isolated in 72% yield.
On the other hand, the intramolecular cycloaddition
approach generally benefits from the entropy, reactivity, and
easy control of the regio- and stereochemistry compared with
the intermolecular version.[10] Particularly, this approach
should be attractive for the asymmetric total synthesis of 1,
because the chiral integrity of the key intermediate would be
easily retained. Herein, we would like to describe the total
synthesis of racemic 1 via our intramolecular cycloaddition
approach (Scheme 1b), which is believed to become an
alternative asymmetric synthesis of 1. The highlight of this
work is the development of the aromatic Pummerer-type
reaction with 1-ethoxyvinyl chloroacetate (7b).[11±13] Use of
this acylating reagent was inevitable for introduction of the
oxygen functional group to the internal B-ring of the highly
functionalized, congested polyaromatic ABC-ring moiety.
Results and Discussion
Despite the above-mentioned advantages of the intramolec-
ular cycloaddition approach, no one has succeeded in the
preparation of the ABC-ring with this approach. A few
approaches have been reported;[14, 15] however, the difficulty
remains in the lack of an effective preparation method for the
highly oxygen-substituted polycyclic aromatic structures.
In order to circumvent this problem, very recently we have
presented a basic concept involving the oxidative intramo-
lecular [4 ‡ 2] cycloaddition reaction of the (phenylthio)acet-
ylene ± cobalt complex 2 to give the cycloadduct 3 and the
subsequent aromatic Pummerer-type reaction to substitute
the sulfinyl group by the oxygen functional group (3 ! 4)
(Scheme 2).[16]
Scheme 3. Aromatic Pummerer-type reaction of 5. a) (CF3CO)2O, styrene,
CHCl3, 08C, 71%; b) 7b, cat. pTsOH, toluene, 1108C, 72% for 8b;
c) 1. Bu4NF, THF/H2O, room temperature, 2. BBr3, CH2Cl2, À78 !
À 458C, 3. 80% CF3CO2H, reflux, 62% from 5a.
These contradicting effects between the acid anhydrides
and the ethoxyvinyl esters seem to be ascribed to the different
nucleophilic nature of the counteranions in the intermediates
(A and B), although we have not sufficiently clarified that yet.
In the reaction with 7b, the nucleophilic attack of the enolate
anion or the excess 7b took place at the sulfur atom of B to
give 8 along with ethyl phenylthioacetate.
With an efficient method at hand, our attention focused
next on the total synthesis of racemic 1. The key intermediate
(10) was obtained from either the known DEF-ring moiety
11[17] or 14[3] in 12% and 51% overall yield, respectively
(Scheme 4). In the latter route, the acetylation of 17 gave a 1:1
mixture of two diastereomers 18, which was hydrolyzed to
(Æ)-10. Direct introduction of acetyl group to 16 or the use of
the N,N-dimethylhydrazone instead of 17 gave lowyields
of 10.
Scheme 2. Synthesis of the ABCD-ring model compound 4. a) 1. Me2-
SiCl2, Et3N, chloranil, 1008C, 2. tBu2Si(OTf)2, Et3N, 3. mCPBA;
b) 1. (CF3CO)2O, styrene, 2. Ac2O, AcONa, pyridine.
However, a similar Pummerer-type reaction of the ABCD-
ring precursor 5a under the standard reaction conditions
(trifluoroacetic anhydride/styrene) did not give the desired
4-type product. Thus, the presence of the methoxy group at
the peri-position of the sulfinyl group of 5 resulted in its
cleavage to give the quinone sulfide 6 (71% yield) as the
single product. After intensive studies involving changing the
acylating reagents, solvents, and additives, we finally found
that the reaction of 5a with 1-ethoxyvinyl chloroacetate (7b)
In order to introduce the (phenylthio)ethynyl group and the
A-ring acyl group into 10, this compound was first treated
with lithium (phenylthio)acetylide (1.1 ± 1.3 equiv) in THF at
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Chem. Eur. J. 2000, 6, No. 21

(Æ)-Fredericamycin A
3897±3905
demethylation to give 28 quantitatively. Oxidation of the
methyl group of the F-ring by SeO2 gave the formyl group
(!29), which was in turn subjected to the usual Wittig reaction
to give 30 (28% yield, a 5:1 mixture of E,E- and Z,E-isomers)
with recovery of a 67% yield of 29. Treatment of 30 with BBr3
removed all protecting groups simultaneously, and the subse-
quent auto-oxidation and separation of the minor impurity of
the diene isomer by HPLC (Jasco Megapak SIL NH2-10, 1 Â
25 cm, CHCl3/hexane/acetic acid 800:200:1, 5 mLminÀ1 flow
rate)[8a] afforded (Æ)-1 (52% yield). The synthetic compound
was identical with an authentic sample of natural frederica-
mycin A (1H NMR, UV, TLC, HPLC) (Scheme 5).
OH
O
OH
MeO MeO
N
CO2Me
CO2Me
OR
a
HN
c
O
12 R = H
11
b
MeO MeO
N
13 R = COPh
CHO
OMe
h
MeO MeO
N
R
X
10
f
N
N
14 X = O
17 R = H
18 R = COMe
g
d
e
H
15 X =
CH2OH
H
16 X =
CHO
20
SPh
Scheme 4. Synthesis of the key intermediate 10. a) 1. MeI, Ag2O, dioxane,
2. LiAlH4, THF, 35% for two steps; b) BzCl, pyridine, CH2Cl2, 45%;
c) 1. Dess ± Martin periodinane, MeCN, 2. MeMgBr, THF, then MeLi, 93%
O
OBn
O
O
MeO MeO
N
Cl
OLi
‡
for two steps, 3. DMSO, (COCl)2, Et3N, CH2Cl2, 80%; d) 1. (Me)Ph3P BrÀ,
R
OMe
OMe
tBuOK, THF, 83%. 2. BH3 ´ THF, THF then H2O2, 2n NaOH, 92%;
e) Dess ± Martin periodinane, CH2Cl2; f) (R)-1-amino-2-(methoxymethyl)-
pyrrolidine, CH2Cl2, 87% for two steps; g) LDA, AcCl, THF, 77%;
h) aqueous (CO2H)2, Et2O, 99%.
21
SPh
a
10 R = CHO
19 R = H
22
BnO
O
À788C for a selective addition to the formyl group; however,
a retro-aldol reaction of the primary adduct 22 took place
while warming the reaction mixture and the chromatography
(silica gel) of the crude product; this results in the formation
of ketone 19 as the major product. Quenching 22 with the
A-ring acid chloride 21 (2 ± 3 equiv) at À78 or À1008C
provided the ester 23 in poor yields. However, addition of
2 equiv LiN(TMS)2 to a solution of 10 (1 equiv), 20 (1 equiv),
and 21 (2 equiv) in THF at À788C followed by gradual
warming the reaction mixture to room temperature caused
the sequential lithium acetylide formation, addition of the
lithium acetylide to the formyl group of 10, and the
esterification of 22 with 21 to afford 23 (69% yield) as a
17:1 mixture of two diastereomers.
We then tried to induce the migration of the A-ring aroyl
group to the methyl ketone terminus under basic conditions.
Thus, the 17:1 diastereomeric mixture of 23 was dissolved in
toluene and treated with LiN(TMS)2 (3 equiv) at room
temperature. After consumption of the major isomer (for
2 ± 3 h), HMPA (3 equiv) was added, and the stirring was
continued at room temperature for another 30 min to
consume the minor isomer to provide 24 (70% yield) as a
17:1 mixture of two diastereomers. This mixture was subjected
to Dess ± Martin oxidation, followed by formation of the
cobalt complex and debenzylation to provide 25.
Similarly to the preparation of 3,[16] the cycloaddition of 25
in the presence of Me2SiCl2 (4 equiv), Et3N (8 equiv), and
chloranil (4 equiv) proceeded in toluene at 1008C to give the
hexacyclic sulfoxide 26 (47% overall yield from 25) after
protection of the peri-diol moiety by the silylene group and
the oxidation of the sulfenyl group. The aromatic Pummerer-
type reaction of 26 with 7b and a catalytic amount of p-TsOH
in refluxing toluene afforded 27 in 77% yield. Demethylation
of the F-ring of 27 with Me3SiI,[3, 5, 8a] gave the expected
pyridone 28 in 40% yield due to the cleavage of relatively
labile protective groups such as bis(tert-butyl)silylene and
chloroacetyl groups. However, the employment of tBu2-
Si(OTf)2, Et3N, and MeI was found to be effective for the
BnO
A
OMe
O
O
O
OMe
SPh
b
O
OMe
OMe
OH
24
SPh
23
c
tBu
O
HO
O
tBu Si
OMe
O
OMe
OMe
A
O
O
B
OMe
SPh
MeO MeO
N
d
C
X
Co2(CO)6
F
D
E
O
O
25
26 X = S(O)Ph
e
27 X = OCOCH2Cl
f
tBu
O
tBu Si
O
OMe
O
O MeO
OMe
OCOCH2Cl
HN
i
O
Y
(±)-1
28 Y = H2
29 Y = O
g
h
30 Y = CH–CH=CH–Me
Scheme 5. Synthesis of racemic fredericamycin A (1). a) 20, 21,
LiN(TMS)2, THF, 69%; b) LiN(TMS)2, toluene then HMPA, 70%;
c) 1. Dess-Martin periodinane, CH2Cl2, 2. Co2(CO)8, CH2Cl2, 84% for
two steps, 3. BCl3, CH2Cl2, 37%; d) 1. Me2SiCl2, Et3N, chloranil, toluene,
2. tBu2Si(OTf)2, Et3N, DMF, 3. mCPBA, CH2Cl2, 47% for three steps;
e) 7b, cat. pTsOH, toluene, 77%; f) tBu2Si(OTf)2, Et3N, MeI, DMF, quant.;
g) SeO2, dioxane, 78%; h) (MeCH CHCH2)Ph3P Br , nBuLi, THF, 28%
(85% based on consumed 29); i) 1. BBr3, CH2Cl2, 2. THF/H2O, air,
3. HPLC separation, 52% for three steps.
‡
À
ˆ
Conclusion
A new, linear synthesis of the highly oxygen-substituted
polyaromatic, fredericamycin A (1) was elucidated by the
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Y. Kita et al.
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127.9, 128.5, 135.8, 142.5, 155.7, 155.9, 162.0. This compound was used for
the preparation of 23 and 32 without prior purification.
combination of the oxidative intramolecular [4 ‡ 2] cyclo-
addition of the suitably functionalized (phenylthio)acety-
lene ± Co2(CO)6 complex 25 and the aromatic Pummerer-type
reaction of the sulfoxide 26 with 1-ethoxyvinyl chloroacetate
(7b). Application of this protocol to the optically pure
intermediate 10 would lead to the total synthesis of natural
1 and its derivatives and is nowin progress in our laboratory.
Sulfoxide (5a) was synthesized as shown in Scheme 6.
SPh 20
O
OBn
O
Cl
O
O
O
O
OMe
OMe
OBn
OMe
21
CHO
a
PhS
b
31
MeO
32
Experimental Section
O
O
OH
OBn
O
O
General techniques: Melting and boiling points are uncorrected. IR-
absorption spectra were recorded as a solution in an organic solvent or by
diffuse reflectance measurement of samples dispersed in KBr powder. 1H-
and 13C-NMR spectra were measured in CDCl3 with SiMe4 or CHCl3 as
internal standards. High-resolution mass spectra (HRMS) were recorded at
70 eV with a direct inlet system. Silica gel BW-300, Fuji Silysia Chemical,
Japan, particle size 38 ± 75 mm, was used for flash column chromatography
and silica gel 60 F254 glass plates, E. Merck, for preparative TLC.
Anhydrous solvents were prepared by the standard methods. Glass
reactors used for the intramolecular [4 ‡ 2] cycloadditions were purchased
from Taiatsu Scientific Glass, Japan.
c
OMe
OMe
S
O
O
S
OMe
OMe
(OC)6Co2
Ph
Ph
33
34
d
5a
Scheme 6. Synthesis of the sulfoxide 5a. a) 1. 20, nBuLi, THF/HMPA,
81%, 2. pTsOH, acetone, 98%, 3. 21, 4-(dimethylamino)pyridine, CH2Cl2,
quant.; b) 1. LiN(TMS)2, THF, 88%, 2. DMSO, DCC, pyridinium trifluoro-
acetate, benzene, 64%; c) 1. Co2(CO)8, CH2Cl2, 82%, 2. BCl3, CH2Cl2,
73%; d) 1. Me2SiCl2, Et3N, chloranil, toluene, 2. tBu2Si(OTf)2, Et3N, DMF,
57%, 3. mCPBA, CH2Cl2, 78%.
Compounds 7a,[11] 7b,[12c] 11,[17] 14,[3] 20,[18] 31,[15] and crotyltriphenylphos-
phonium bromide[19] were prepared as previously reported.
1-Ethoxyvinyl dichloroacetate (7c): Under a nitrogen atmosphere, a
solution of dichloroacetic acid (1.32 mL, 16 mmol) in anhydrous THF
(12 mL) was slowly added to an ice-cooled solution of ethoxyacetylene
(2.0 mL, 24 mmol) and [RuCl2(p-cymene)]2 (30 mg, 0.048 mmol) in anhy-
drous THF (10 mL) over a period of 15 min. After being stirred at 08C for
2 h, the reaction mixture was concentrated in vacuo at room temperature,
and the residue was purified by distillation to give 7c (1.94 g, 61%) as a
yellowoil. B.p. 90 ± 91 8C/19 Torr; IR (THF): nĈ 1794, 1678 cmÀ1; 1H NMR
(270 MHz, CDCl3): d ˆ 1.36 (t, 3H, J ˆ 7.0 Hz), 3.86 (d, 1H, J ˆ 4.0 Hz),
3.92 (q, 2H, J ˆ 7.0 Hz), 3.98 (d, 1H, J ˆ 4.0 Hz), 6.01 (s, 1H); HRMS: anal.
calcd for C6H8Cl2O3: 197.9850; found 197.9865.
4,4-Tetramethylene-5-oxo-1-phenylthio-1-hexyn-3-yl 2-benzyloxy-4,5-di-
methoxy benzoate (32): Under a nitrogen atmosphere, nBuLi (1.6m
solution in hexane, 36 mL, 59 mmol) and anhydrous HMPA (10 mL,
59 mmol) were added to a solution of 20 (7.9 g, 59 mmol) in anhydrous THF
(70 mL) at À508C. The reaction mixture was stirred at À508C for 30 min,
to which was added a solution of 31 (9.8 g, 54 mmol) in anhydrous THF
(70 mL). The reaction mixture was stirred at À508C for 40 min, and the
cooling bath was removed. The reaction mixture was warmed to room
temperature and then poured into saturated aqueous NH4Cl. The aqueous
layer was extracted with EtOAc and the combined organic layer was
washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane/EtOAc 5:1 ! 3:1)
to give 5,5-ethylenedioxy-3-hydroxy-4,4-tetramethylene-1-phenylthio-1-
hexyne (13.7 g, 81%) as a pale yellowoil. IR (KBr): nĈ 3700 ± 3000,
1-Ethoxyvinyl trichloroacetate (7d): Similar to the preparation of 7c, 7d
(1.36 g, 73%) was prepared from trichloroacetic acid (1.31 g, 8.0 mmol) to
yield a yellowoil. B.p. 85 ± 86 8C/17 Torr; IR (THF): nĈ 1796, 1676 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 1.38 (t, 3H, J ˆ 7.0 Hz), 3.90 (d, 1H, J ˆ
4.5 Hz), 3.96 (q, 2H, J ˆ 7.0 Hz), 4.04 (d, 1H, J ˆ 4.5 Hz); elemental
analysis calcd for C6H7Cl3O3: C 30.87, H 3.02; found C 31.05, H 3.05.
2-Benzyloxy-4,5-dimethoxybenzoyl chloride (21): NaClO2 (4.9 g, 54 mmol)
was added to a mixture of 2-benzyloxy-4,5-dimethoxybenzaldehyde (11.3 g,
42 mmol), NaH2PO4 (12.5 g, 104 mmol), 2-methyl-2-butene (22 mL,
0.21 mol), tBuOH (700 mL), and water (100 mL). The reaction mixture
was stirred at room temperature overnight and concentrated in vacuo to
one-forth of its volume. The residue was poured into a mixture of water and
CH2Cl2. The organic layer was separated and extracted with 10% NaOH
(2 Â ). The aqueous layer was acidified with 10% HCl to pH 2 ± 3 and
extracted with CH2Cl2 (5 Â ). The combined organic layer was dried
(Na2SO4) and concentrated in vacuo. Recrystallization of the residual solid
from ClCH2CH2Cl gave 2-benzyloxy-4,5-dimethoxybenzoic acid (9.8 g,
61%) as colorless crystals. M.p. 72 ± 748C (ClCH2CH2Cl); IR (KBr): nĈ
3400 ± 2400, 1732, 1682, 1609, 1576 cmÀ1; 1H NMR (270 MHz, CDCl3): d ˆ
3.90 (s, 3H), 3.91 (s, 3H), 5.28 (s, 2H), 6.61 (s, 1H), 7.42 ± 7.44 (m, 5H), 7.63
(s, 1H), 10.76 (brs, 1H); 13C NMR (68 MHz, CDCl3): d ˆ 56.28, 56.31, 73.2,
97.8, 109.5, 114.1, 127.9, 129.1, 129.2, 134.2, 144.1, 152.6, 153.9, 165.0;
elemental analysis calcd for C16H16O5: C 66.66, H 5.59; found C 66.63, H
5.60.
1705, 1584 cmÀ1; H NMR (270 MHz, CDCl3): d ˆ 1.36 (s, 3H), 1.66 ± 1.78
1
(m, 8H), 4.00 ± 4.10 (m, 4H), 4.19 (d, 1H, J ˆ 2.0 Hz), 4.87 (d, 1H, J ˆ
2.0 Hz), 7.20 ± 7.45 (m, 5H); HRMS: anal. calcd for C18H22O3S: 318.1290;
found 318.1288.
A mixture of the above product (13.7 g, 43 mmol) and p-toluenesulfonic
acid ´ H2O (0.82 g, 4.3 mmol) in acetone (360 mL) was stirred at room
temperature for 1 h. The reaction mixture was concentrated in vacuo to a
half of its volume and poured into saturated aqueous NaHCO3. The
aqueous layer was extracted with EtOAc (3 Â ), and the combined organic
layer was washed with brine, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography (hexane/EtOAc
3:1 ! 1:1) to give 3-hydroxy-4,4-tetramethylene-1-phenylthio-1-hexyn-5-
one (11.6 g, 98%) as a pale yellowoil. IR (KBr): nĈ 3700 ± 3000, 2181,
1703, 1582 cmÀ1; 1H NMR (200 MHz, CDCl3): d ˆ 1.65 ± 2.13 (m, 8H), 2.23
(s, 3H), 3.28 (d, 1H, J ˆ 7.0 Hz), 4.68 (d, 1H, J ˆ 7.0 Hz), 7.20 ± 7.43 (m, 5H);
elemental analysis calcd for C16H18O2S: C 70.04, H 6.61, S 11.68; found C
69.76, H 6.60, S 11.57.
A mixture of the above acid (2.0 g, 6.9 mmol) and SOCl2 (15 mL) was
heated under reflux for 8 h. After cooling under a nitrogen atmosphere, the
reaction mixture was concentrated in vacuo. Anhydrous toluene (5 mL)
was added, and the mixture was concentrated in vacuo and dried under
vacuum (0.1 Torr) at room temperature for 2 h to give 21 as a yellowsolid.
IR (CH2Cl2): nĈ 1763, 1611, 1572, 1514 cmÀ1; 1H NMR (270 MHz, CDCl3):
d ˆ 3.89 (s, 6H), 5.18 (s, 2H), 6.51 (s, 1H), 7.28 ± 7.49 (m, 5H), 7.62 (s, 1H);
13C NMR (68 MHz, CDCl3): d ˆ 56.3, 56.4, 71.4, 98.3, 112.9, 116.6, 126.8,
Under a nitrogen atmosphere, a solution of the above product (1.27 g,
4.6 mmol) and 4-(dimethylamino)pyridine (2.8 g, 23 mmol) in anhydrous
CH2Cl2 (50 mL) was stirred at 08C for 30 min, to which was added a
solution of the crude acid chloride (21) [prepared from the corresponding
carboxylic acid (2.0 g, 6.9 mmol)] in anhydrous CH2Cl2 (40 mL). The
reaction mixture was stirred at room temperature for 2 h and poured into
saturated aqueous NH4Cl. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2. The combined organic layer was
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Chem. Eur. J. 2000, 6, No. 21

(Æ)-Fredericamycin A
3897±3905
washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane/EtOAc 6:1) to give
atmosphere, 34 (16 mg, 19 mmol) and anhydrous toluene (2.0 mL) were
placed in a glass reactor, and Et3N (22 mL, 0.16 mmol), Me2SiCl2 (10 mL,
77 mmol), and chloranil (19 mg, 77 mmol) were added successively. The
reactor was sealed and heated at 1008C for 12 h. After cooling, the reaction
mixture was transferred to a round-bottomed flask and concentrated in
32 (2.6 g, quant.) as a brown oil. IR (KBr): nĈ 1725, 1709, 1613, 1582 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 1.58 ± 1.70 (m, 4H), 1.86 ± 1.97 (m, 3H),
2.18 ± 2.24 (m, 1H), 2.24 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H), 5.15 (s, 2H), 6.16
(s, 1H), 6.49 (s, 1H), 7.21 (dd, 1H, J ˆ 8.0, 6.5 Hz), 7.27 ± 7.47 (m, 10H);
elemental analysis calcd for C32H32O6S: C 70.57, H 5.92, S 5.89; found C
70.39, H 6.02, S 5.84.
vacuo. Under
a nitrogen atmosphere, the residue was dissolved in
anhydrous DMF (1.0 mL), and Et3N (0.10 mL, 0.72 mmol), and tBu2-
Si(OTf)2 (0.12 mL, 0.34 mmol) were added. The reaction mixture was
stirred at room temperature overnight and cooled to 08C. Saturated
aqueous NaHCO3 and Et2O were added, and the organic layer was
separated. The aqueous layer was extracted with Et2O (5 Â ), and the
combined organic layer was washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified twice by flash column
chromatography with different eluents (hexane/CH2Cl2 3:1 ! 1:1 and
hexane/EtOAc 10:1) to give 4,5-[di(tert-butyl)silylenedioxy]-7,8-dimeth-
oxy-2,2-tetramethylene-9-phenylthio-2,3-dihydrobenz[f]indene-1,3-dione
1-(2-Benzyloxy-4,5-dimethoxyphenyl)-4,4-tetramethylene-7-phenylthio-6-
heptyne-1,3,5-trione (33): Under a nitrogen atmosphere, LiN(TMS)2 (1.0m
solution in THF, 11.3 mL, 11.3 mmol) was added to a solution of 32 (2.1 g,
3.8 mmol) in anhydrous THF (35 mL) at À788C. The reaction mixture was
stirred at À788C for 30 min, and the cooling bath was removed. The
reaction mixture was warmed to room temperature and poured into
saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc
(2 Â ), and the combined organic layer was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by flash
column chromatography (hexane/EtOAc 4:1) to give 1-(2-benzyloxy-4,5-
dimethoxyphenyl)-5-hydroxy-4,4-tetramethylene-7-phenylthio-6-heptyne-
1,3-dione (1.82 g, 88%) as pale yellowcrystals. M.p. 102 ± 103 8C (hexane/
(6.5 mg, 57%) as a yellowoil. IR (KBr): nĈ 1730, 1701, 1603, 1574 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 1.17 (s, 18H), 1.52 ± 1.77 (m, 8H), 3.95 (s,
3H), 4.00 (s, 3H), 6.93 (s, 1H), 7.15 ± 7.17 (m, 5H); HRMS: anal. calcd for
C33H38O6SSi: 590.2158: found 590.2152.
Et2O); IR (KBr): nĈ 3600 ± 3200, 1615, 1518 cmÀ1
;
1H NMR (500 MHz,
Under a nitrogen atmosphere, mCPBA (80% purity, 43 mg, 0.20 mmol)
was added to a solution of the above product (118 mg, 0.20 mmol) in
anhydrous CH2Cl2 (5 mL) at À788C, and the reaction mixture was stirred
at À408C for 30 min. Saturated aqueous Na2S2O3 was added, and the
mixture was vigorously stirred at room temperature for 10 min. The organic
layer was separated, and the aqueous layer was extracted with CH2Cl2. The
combined organic layer was washed with saturated aqueous NaHCO3,
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc 10:1 ! 1:1) to give 5a
CDCl3): d ˆ 1.26 ± 1.99 (m, 8H), 3.65 (d, 1H, J ˆ 8.5 Hz), 3.92 (s, 3H), 3.94
(s, 3H), 4.43 (d, 1H, J ˆ 8.5 Hz), 5.02 (d, 1H, J ˆ 10.0 Hz), 5.05 (d, 1H, J ˆ
10.0 Hz), 6.59 (s, 1H), 6.72 (s, 1H), 7.13 (t, 1H, J ˆ 7.5 Hz), 7.22 ± 7.41 (m,
9H), 7.58 (s, 1H), 16.63 (s, 1H); elemental analysis calcd for C32H32O6S: C
70.57, H 5.92, S 5.89; found C 70.51, H 5.96, S 5.80.
Under a nitrogen atmosphere, a solution of the above product (27 mg,
49 mmol) in anhydrous benzene (2.0 mL) was cooled to 08C, and DMSO
(42 mL, 0.59 mmol), dicyclohexylcarbodiimide (DCC) (61 mg, 0.30 mmol),
and pyridinium trifluoroacetate (9.4 mg, 50 mmol) were added successively.
The reaction mixture was stirred at room temperature for 1 h and poured
into water. The organic layer was extracted with Et2O (2 Â ), and the
combined organic layer was washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by flash column
chromatography (hexane/EtOAc 4:1) to give 33 (17.1 mg, 64%) as yellow
crystals. M.p. 148 ± 1498C (hexane/Et2O); IR (KBr): nĈ 2116, 1615,
(94 mg, 78%) as a yellowoil. IR (KBr): nĈ 1744, 1711, 1605, 1568 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 1.16 (s, 9H), 1.17 (s, 9H), 1.86 ± 2.05 (m,
8H), 3.74 (s, 3H), 4.02 (s, 3H), 6.94 (s, 1H), 7.39 ± 7.45 (m, 3H), 7.79 (d, 2H,
J ˆ 7.0 Hz); HRMS: anal. calcd for C33H38O7SSi: 606.2107; found 606.2107.
4,5-[Di(tert-butyl)silylenedioxy]-8-methoxy-2,2-tetramethylene-9-phenyl-
sulfinyl-2,3-dihydrobenz[f]indene-1,3-dione (5b): Compound 5b was pre-
pared similar to the reported method[9c] to yield a yellowoil. IR (KBr): nĈ
1742, 1713, 1605, 1586 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 1.15 (s, 9H),
1.16 (s, 9H), 1.87 ± 2.10 (m, 8H), 3.68 (s, 3H), 7.05 (d, 1H, J ˆ 8.5 Hz), 7.09
(d, 1H, J ˆ 8.5 Hz), 7.42 ± 7.50 (m, 3H), 7.72 ± 7.74 (m, 2H); HRMS: anal.
calcd for C32H36O6SSi: 576.2002; found 576.1996.
1518 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 1.53 ± 1.56 (m, 4H), 1.94 ±
1.97 (m, 2H), 2.16 ± 2.19 (m, 2H), 3.89 (s, 3H), 3.91 (s, 3H), 5.08 (s, 2H),
6.57 (s, 1H), 6.67 (s, 1H), 7.25 ± 7.41 (m, 10H), 7.52 (s, 1H), 16.23 (s, 1H);
elemental analysis calcd for C32H30O6S: C 70.83, H 5.57, S 5.91; found C
70.76, H 5.53, S 5.92.
4-Hydroxy-7-methoxy-2,2-tetramethylene-9-phenylthio-2,3-dihydrobenz-
[f]indene-1,3,5,8-tetrone (6): Under a nitrogen atmosphere, trifluoroacetic
anhydride (32 mL, 0.23 mmol) was added to an ice-cooled solution of 5a
(14.0 mg, 23 mmol) and styrene (7.9 mL, 69 mmol) in CHCl3 (1.5 mL). The
reaction mixture was stirred at 08C for 30 min and concentrated in vacuo.
The residue was purified by preparative TLC (hexane/EtOAc 1:1) to give 6
(7.1 mg, 71%) as dark-blue crystals. M.p. 244 ± 2468C (hexane/EtOAc); IR
(KBr): nĈ 1748, 1715, 1669, 1621, 1607 cmÀ1; 1H NMR (500 MHz, CDCl3):
d ˆ 1.43 ± 1.76 (m, 8H), 4.00 (s, 3H), 6.24 (s, 1H), 7.05 ± 7.18 (m, 5H), 13.74
(s, 1H); HRMS: anal. calcd for C24H18O6S: 434.0824; found 434.0820.
{1-(2-Hydroxy-4,5-dimethoxyphenyl)-4,4-tetramethylene-7-phenylthio-6-
heptyne-1,3,5-trione}hexacarbonyldicobalt (34): Under a nitrogen atmos-
phere, Co2(CO)8 (180 mg, 0.52 mmol) was added to an ice-cooled solution
of 33 (140 mg, 0.26 mmol) in anhydrous CH2Cl2 (5 mL), and the flask was
covered with aluminum foil. The reaction mixture was stirred at 08C for
30 min and then at room temperature for another 30 min. Silica gel for flash
column chromatography (2 g) was added to the reaction mixture and the
whole mixture was concentrated in vacuo. The crude product absorbed on
the silica gel was purified by flash column chromatography (hexane/EtOAc
2:1) to give {1-(2-benzyloxy-4,5-dimethoxyphenyl)-4,4-tetramethylene-7-
phenylthio-6-heptyne-1,3,5-trione}hexacarbonyldicobalt (174 mg, 82%) as
9-Chloroacetoxy-4,5-[di(tert-butyl)silylenedioxy]-7,8-dimethoxy-2,2-tetra-
methylene-2,3-dihydrobenz[f]indene-1,3-dione (8a): Under
a nitrogen
a dark-brown gum. IR (KBr): nĈ 2099, 2062, 2037, 1576 cmÀ1
;
1H NMR
atmosphere, 7b (29 mL, 0.17 mmol) and anhydrous p-toluenesulfonic acid
(1.5 mg, 8.7 mmol) were added to a solution of 5a (21 mg, 35 mmol) in
anhydrous toluene (2.0 mL). The flask was set in an oil bath, pre-heated at
1108C, and stirred for 3.5 h. After cooling, Et3N (one drop) was added, and
the reaction mixture was concentrated in vacuo to give crude 8a. Due to
partial decomposition of 8a during flash column chromatography, the
crude product was used for the following step without prior purification.
Analytically pure 8a was obtained by flash column chromatography twice
with different eluents (hexane/EtOAc 5:1 then hexane/benzene 3:1 ! 1:1)
(270 MHz, CDCl3): d ˆ 1.56 ± 1.61 (m, 4H), 2.01 ± 2.07 (m, 2H), 2.26 ± 2.31
(m, 2H), 4.10 (s, 3H), 4.13 (s, 3H), 5.11 (s, 2H), 6.56 (s, 1H), 6.78 (s, 1H),
7.38 ± 7.55 (m, 11H), 16.29 (s, 1H).
Under a nitrogen atmosphere, BCl3 (1.0m solution in CH2Cl2, 0.30 mL,
0.30 mmol) was added to an ice-cooled solution of the above product
(125 mg, 0.15 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at
08C for 5 min and then at room temperature for 10 min and poured into
ice-water. The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layer was washed with brine,
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc 3:1) to give 34 (81 mg, 73%)
1
as a yellowoil. IR (KBr): nĈ 1790, 1732, 1707, 1605, 1582 cmÀ1; H NMR
(270 MHz, CDCl3): d ˆ 1.15 (s, 18H), 1.93 ± 2.05 (m, 8H), 3.86 (s, 3H), 4.00
(s, 3H), 4.52 (s, 2H), 6.92 (s, 1H); HRMS: anal. calcd for C29H35ClO8Si:
574.1790; found 574.1790.
as a dark-brown gum. IR (KBr): nĈ 2099, 2066, 2041, 1667, 1632, 1574 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 1.77 ± 1.85 (m, 4H), 2.19 ± 2.29 (m, 2H),
2.50 ± 2.59 (m, 2H), 3.82 (s, 3H), 3.90 (s, 3H), 6.20 (s, 1H), 6.43 (s, 1H), 6.98
(s, 1H), 7.38 ± 7.58 (m, 5H), 12.08 (s, 1H), 15.60 (s, 1H).
9-Chloroacetoxy-4,5-[di(tert-butyl)silylenedioxy]-8-methoxy-2,2-tetra-
methylene-2,3-dihydrobenz[f]indene-1,3-dione (8b): Similar to the prepa-
ration of 8a, 5b (28 mg, 49 mmol) was heated with 7b (40 mL, 0.24 mmol) at
1108C for 4.5 h. The product was purified by flash column chromatography
twice with different eluents (hexane/EtOAc 5:1 then benzene) to give 8b
4,5-[Di(tert-butyl)silylenedioxy]-7,8-dimethoxy-2,2-tetramethylene-9-
phenylsulfinyl-2,3-dihydrobenz[f]indene-1,3-dione (5a): Under a nitrogen
Chem. Eur. J. 2000, 6, No. 21
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0621-3901 $ 17.50+.50/0
3901

Y. Kita et al.
FULL PAPER
(19 mg, 72%) as a yellowoil. IR (KBr): nĈ 1788, 1732, 1709, 1607 cmÀ1
;
(62 mg, 0.15 mmol) was added to an ice-cooled solution of 13 (49 mg,
0.12 mmol) in acetonitrile (2.0 mL). The reaction mixture was stirred at
room temperature for 5 h and poured into a saturated aqueous Na2S2O3
solution. The product was extracted with EtOAc (2 Â ), and the combined
organic layer was washed with a saturated aqueous NaHCO3, dried
(Na2SO4), and concentrated in vacuo to give (8-formyl-1,9-dimethoxy-3-
methyl-6,7-dihydro-8H-cyclopent[g]isoquinolin-8-yl)methyl benzoate as a
colorless oil. This product was used for the next reaction without further
1H NMR (CDCl3): d ˆ 1.14 (s, 18H), 1.93 ± 1.96 (m, 8H), 3.91 (s, 3H), 4.51
(s, 2H), 6.98 (d, 1H, J ˆ 8.5 Hz), 7.06 (d, 1H, J ˆ 8.5 Hz); HRMS: anal.
calcd for C28H33ClO8Si: 544.1684; found 544.1697.
4,9-Dihydroxy-7-methoxy-2,2-tetramethylene-2,3-dihydrobenz[f]indene-
1,3,5,8-tetrone (9): A solution of the crude 8a obtained above in THF
(2 mL) and water (0.4 mL) was cooled to 08C, to which was added Bu4NF
(1.0m solution in THF, 10 mL, 10 mmol). The reaction mixture was stirred at
room temperature for 40 min and poured into brine. The aqueous layer was
extracted with CH2Cl2, and the combined organic layer was washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was dried
under vacuum (0.1 Torr) at room temperature for 2 h and dissolved in
anhydrous CH2Cl2 (2 mL). Under a nitrogen atmosphere, BBr3 (1.0m
solution in CH2Cl2, 0.17 mL, 0.17 mmol) was added to this solution at
À788C, and the reaction mixture was gradually warmed, with stirring, to
À458C over a period of 3.5 h and then poured into ice-water. The aqueous
layer was extracted with CH2Cl2 (2 Â ), and the combined organic layer was
washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue
was heated in CF3COOH (3.0 mL) and water (0.75 mL) under reflux for
3 h, cooled, and concentrated in vacuo. The residue was purified by flash
column chromatography (CH2Cl2 ! CH2Cl2/EtOAc/AcOH 400:200:1) to
give 9 (7.3 mg, 62% from 5a, as dark red crystals. M.p. 248 ± 2508C (lit.[20]
purification. IR (KBr): nĈ 1727, 1628, 1568 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d ˆ 2.23 ± 2.32 (m, 1H), 2.51 (s, 3H), 2.60 ± 2.71 (m, 1H), 3.10 ± 3.27
(m, 2H), 3.89 (s, 3H), 4.14 (s, 3H), 4.67 (d, 1H, J ˆ 11.5 Hz), 5.15 (d, 1H,
J ˆ 11.5 Hz), 6.98 (s, 1H), 7.30 (s, 1H), 7.41 (t, 2H, J ˆ 8.0 Hz), 7.55 (t, 1H,
J ˆ 8.0 Hz), 7.93 (d, 2H, J ˆ 8.0 Hz), 9.92 (s, 1H).
Under a nitrogen atmosphere, a solution of the above crude product in
THF (3.0 mL) was cooled to À788C, and MeMgBr (0.83m solution in THF,
0.50 mL, 0.42 mmol) was added. The reaction mixture was stirred at À788C
for 1.5 h, and MeLi (1.1m solution in hexane, 0.38 mL, 0.42 mmol) was
added. The reaction mixture was stirred at À788C for 10 min, warmed to
08C, and stirred at 08C for 30 min. The reaction mixture was poured into a
saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was
dried (Na2SO4) and concentrated in vacuo. Purification of the residue by
flash column chromatography (hexane/EtOAc 3:1) gave 8-(1-hydroxyeth-
yl)-8-hydroxymethyl-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopent-
[g]isoquinoline (a 17:3 mixture of two diastereomers, 36 mg, 93% from 13)
m.p. 247 ± 2498C); IR (CH2Cl2): nĈ 1750, 1715, 1692, 1611, 1563 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 1.96 ± 2.17 (m, 8H), 3.99 (s, 3H), 6.28 (s,
1H), 12.50 (brs, 1H), 13.15 (s, 1H); HRMS: anal. calcd for C18H14O7:
342.0740; found 342.0756.
as a colorless oil. IR (KBr): nĈ 3700 ± 3100, 1628, 1615, 1565, 1559 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 1.02 (d, 9/20H, J ˆ 6.5 Hz), 1.14 (d, 51/
20H, J ˆ 6.5 Hz), 1.93 ± 2.21 (m, 2H), 2.25 ± 2.42 (m, 3/20H), 2.49 (s, 3H),
2.59 (dd, 17/20H, J ˆ 8.5, 5.0 Hz), 2.83 ± 2.87 (m, 3/20H), 3.02 (dd, 2H, J ˆ
8.5, 7.5 Hz), 3.19 (d, 17/20H, J ˆ 8.5 Hz), 3.73 (dd, 17/20H, J ˆ 11.0, 8.5 Hz),
3.90 (s, 9/20H), 3.95 (s, 51/20H), 4.02 ± 4.22 (m, 43/20H), 4.13 (s, 3H), 6.94
(s, 1H), 7.24 (s, 1H); HRMS: anal. calcd for C18H23NO4: 317.1627; found
317.1620.
Preparation of 10 from 11:
8,8-Bis(hydroxymethyl)-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclo-
pent[g]isoquinoline (12): Under a nitrogen atmosphere, a mixture of 11
(5.0 mg, 15 mmol), Ag2O (27 mg, 0.12 mmol), MeI (0.20 mL, 3.2 mmol) in
anhydrous dioxane (1.0 mL) was stirred at 658C for 3 h. The reaction
mixture was filtered through a Celite pad, and the filtrate was concentrated
in vacuo. The residue was purified by preparative TLC (hexane/EtOAc 1:1)
to give dimethyl 1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopent[g]iso-
quinoline-8,8-dicarboxylate (3.1 mg) as a colorless oil. IR (KBr): nĈ 1732,
1630, 1570 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 2.48 (s, 3H), 2.83 (t, 2H,
J ˆ 7.0 Hz), 3.03 (t, 2H, J ˆ 7.0 Hz), 3.79 (s, 6H), 3.87 (s, 3H), 4.11 (s, 3H),
6.94 (s, 1H), 7.22 (s, 1H); HRMS: anal. calcd for C19H21NO6: 359.1369;
found 359.1369.
Under
a nitrogen atmosphere, a mixture of oxalyl chloride (29 mL,
0.33 mmol) and DMSO (47 mL, 0.66 mmol) in anhydrous CH2Cl2
(2.0 mL) was stirred at À788C for 10 min, to which was added a solution
of the above product (26 mg, 82 mmol) in anhydrous CH2Cl2 (1.5 mL). The
reaction mixture was stirred at À788C for 1 h, and Et3N (0.14 mL,
0.98 mmol) was added. The reaction mixture was stirred at À788C for 1 h,
gradually warmed to room temperature, and stirred at room temperature
for 30 min. The reaction mixture was poured into saturated aqueous NH4Cl
and extracted with CH2Cl2. The combined organic layer was washed with
brine, dried (Na2SO4), and concentrated in vacuo. Purification of the
residue by flash column chromatography (hexane/EtOAc 3:1) gave 10
(21 mg, 80%) as a pale yellowoil. IR (KBr): nĈ 1728, 1705, 1628,
1611 cmÀ1; 1H NMR (CDCl3): d ˆ 2.21 (s, 3H), 2.33 (ddd, 1H, J ˆ 13.0, 8.5,
5.0 Hz), 2.50 (s, 3H), 2.75 (ddd, 1H, J ˆ 13.0, 7.0, 6.0 Hz), 3.06 ± 3.19 (m,
2H), 3.85 (s, 3H), 4.13 (s, 3H), 6.97 (s, 1H), 7.28 (s, 1H), 10.04 (s, 1H);
13C NMR (68 MHz, CDCl3): d ˆ 23.5, 26.5, 30.7, 31.3, 53.4, 63.5, 74.0, 110.8,
112.5, 117.3, 129.9, 143.2, 148.2, 149.2, 153.8, 158.5, 196.8, 206.4; HRMS
Under a nitrogen atmosphere, LiAlH4 (3.0 mg, 90 mmol) was added to an
ice-cooled solution of the above product (3.1 mg) in THF (1.0 mL). The
reaction mixture was stirred at 08C for 20 min and poured into a saturated
aqueous solution of Rochelle salt. The product was extracted with EtOAc
(3 Â ). The combined organic layer was washed with brine, dried (MgSO4),
and concentrated in vacuo. Purification of the residue by preparative TLC
(hexane/EtOAc 1:2) to give 12 (1.6 mg, 35% from 11) as colorless crystals.
M.p. 139 ± 1408C (hexane/EtOAc); IR (KBr): nĈ 3600 ± 3100, 1628, 1612,
1565 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 2.09 (t, 2H, J ˆ 7.0 Hz), 2.49 (s,
3H), 2.86 ± 2.96 (m, 2H), 3.01 (t, 2H, J ˆ 7.0 Hz), 3.71 ± 3.80 (m, 2H), 3.93
(s, 3H), 3.99 ± 4.13 (m, 2H), 4.14 (s, 3H), 6.94 (s, 1H), 7.26 (s, 1H); 13C NMR
(75 MHz, CDCl3): d ˆ 23.7, 29.8, 31.5, 53.4, 56.4, 64.1, 66.5, 110.8, 112.7,
117.8, 134.7, 142.6, 148.8, 149.7, 153.7, 158.6; elemental analysis calcd for
C17H21NO4: C 67.31, H 6.98, N 4.62; found C 67.13, H 6.84, N 4.57.
‡
(FAB): anal. calcd for C18H20NO4: 314.1393 [M ‡ H] ; found 314.1396.
Preparation of 10 from 14:
8-Hydroxymethyl-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopent[g]-
isoquinoline (15): Under a nitrogen atmosphere, tBuOK (6.1 g, 53 mmol)
was added to a suspension of methyltriphenylphosphonium bromide
(18.9 g, 53 mmol) in anhydrous THF (130 mL) at room temperature, and
the reaction mixture was stirred at room temperature for 1 h. A solution of
14 (6.8 g, 26 mmol) in anhydrous THF (85 mL) was added, and the reaction
mixture was stirred at room temperature for 2 h. Water (100 mL) was
added, and the mixture was concentrated in vacuo to a half of its volume.
The product was extracted with CH2Cl2 (3 Â ), and the combined organic
layer was washed with brine, dried (Na2SO4), and concentrated in vacuo.
Purification of the residue by flash column chromatography (hexane/
EtOAc 20:1) gave 1,9-dimethoxy-3-methyl-8-methylene-6,7-dihydro-8H-
cyclopent[g]isoquinoline (5.6 g, 83%) as a colorless solid. M.p. 90 ± 90.58C
[8-(Hydroxymethyl)-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopent-
[g]isoquinolin-8-yl]methyl benzoate (13): Under a nitrogen atmosphere,
benzoyl chloride (10 mL, 86 mmol) was added to an ice-cooled solution of 12
(23 mg, 77 mmol) and pyridine (10 mL, 0.12 mmol) in anhydrous CH2Cl2
(4.0 mL). The reaction mixture was stirred at room temperature for 3 d and
poured into an aqueous NaHCO3 solution. The product was extracted with
EtOAc (2 Â ), and the combined organic layer was dried (Na2SO4) and
concentrated in vacuo. Purification of the residue by preparative TLC
(hexane/EtOAc 1:1) to give 13 (14 mg, 45%) as a colorless oil. IR (KBr):
nĈ 3600 ± 3100, 1723, 1717, 1628, 1615, 1565 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d ˆ 2.07 ± 2.33 (m, 2H), 2.50 (s, 3H), 2.94 (brs, 1H), 3.03 ± 3.15 (m,
2H), 3.94 (s, 3H), 3.97 ± 4.11 (m, 2H), 4.14 (s, 3H), 4.62 (d, 1H, J ˆ
11.0 Hz), 4.79 (d, 1H, J ˆ 11.0 Hz), 6.96 (s, 1H), 7.27 (s, 1H), 7.41 (dd,
2H, J ˆ 8.0, 7.5 Hz), 7.55 (t, 1H, J ˆ 7.5 Hz), 7.96 (d, 2H, J ˆ 8.0 Hz);
HRMS: anal. calcd for C24H25NO5: 407.1732; found 407.1733.
(hexane/EtOAc); IR (KBr): nĈ 1614, 1565 cmÀ1
;
1H NMR (CDCl3): d ˆ
2.48 (s, 3H), 2.83 ± 2.85 (m, 2H), 3.01 ± 3.04 (m, 2H), 3.87 (s, 3H), 4.14 (s,
3H), 5.30 (s, 1H), 6.07 (s, 1H), 6.91 (s, 1H), 7.22 (s, 1H); 13C NMR
(75 MHz, CDCl3): d ˆ 23.8, 29.9, 32.7, 53.7, 60.5, 109.0, 119.9, 112.7, 117.3,
130.6, 142.2, 147.4, 148.8, 151.2, 154.4, 159.9; C16H17NO2: anal. calcd for C
75.27, H 6.71, N 5.49; found C 74.99, H 6.85, N 5.21.
8-Acetyl-8-formyl-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopent[g]-
isoquinoline (10): Under a nitrogen atmosphere, Dess ± Martin periodinane
3902
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0947-6539/00/0621-3902 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 21

(Æ)-Fredericamycin A
3897±3905
Under a nitrogen atmosphere, BH3 ´ THF complex (1.0m solution in THF,
50 mL, 50 mmol) was added to a solution of the above product (12.5 g,
49 mmol) in anhydrous THF (200 mL) over a period of 5 min. The reaction
mixture was stirred at room temperature for 30 min and cooled to 08C. 2n
NaOH (100 mL) was added dropwise over a period of 20 min, and then
30% aqueous H2O2 (40 mL) was added over a period of 5 min. The
reaction mixture was vigorously stirred at room temperature for 30 min and
extracted with EtOAc (3 Â ). The combined organic layer was washed with
saturated aqueous Na2S2O3 twice, dried (MgSO4), and concentrated in
vacuo. Recrystallization of the residual solid from hexane/EtOAc 1:1 gave
15 (7.0 g). The mother liquor was concentrated in vacuo, and the residue
was recrystallized from the same solvent system to give 15 (4.0 g). The
mother liquor was concentrated in vacuo, and purified by flash column
chromatography (hexane/EtOAc 2:1) to yield another batch of colorless
crystals (1.27 g) (total 92% yield). M.p. 111 ± 111.58C (hexane/EtOAc); IR
7.07 (s, 1/2H), 7.235 (s, 1/2H), 7.240 (s, 1/2H); HRMS (FAB): anal. calcd for
C24H32N3O4: 426.2393 [M ‡ H] ; found 426.2392.
‡
8-Acetyl-8-formyl-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopent[g]-
isoquinoline (10): A mixture of 18 (1.41 g, 3.4 mmol), Et2O (60 mL), and
saturated aqueous oxalic acid (60 mL) was vigorously stirred at room
temperature for 1 h. The organic layer was separated, and the aqueous
layer was extracted with Et2O (7 Â ). The combined organic layer was
successively washed with saturated aqueous NH4Cl (3 Â ) and brine, dried
(Na2SO4), and concentrated in vacuo. Purification of the residue by flash
column chromatography (hexane/EtOAc 4:1) gave 10 (1.05 g, 99%) as a
pale yellow oil. This product was identical with that obtained from 11.
8-Acetyl-8-[1-(2-benzyloxy-4,5-dimethoxybenzoyloxy)-3-phenylthio-2-
propyn-1-yl]-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopent[g]isoquin-
oline (23): Under a nitrogen atmosphere, LiN(TMS)2 (1.0m solution in
THF, 2.7 mL, 2.7 mmol) was added to a solution of 10 (0.40 g, 1.3 mmol), 20
(0.17 g, 1.3 mmol), 21 [in situ prepared from 2-benzyloxy-4,5-dimethoxy-
benzoic acid (0.90 g, 3.1 mmol)] in THF (25 mL) at À788C. The reaction
mixture was stirred at À788C for 2 h, gradually warmed to À208C over a
period of 30 min, and poured into saturated aqueous NH4Cl. The organic
layer was separated, and the aqueous layer was extracted with CH2Cl2. The
combined organic layer was washed with brine, dried (Na2SO4), and
concentrated in vacuo. Purification of the residue by flash column
chromatography (hexane/EtOAc 2:1) gave 23 (0.63 g, 69%) as a separable
mixture of two diastereomers in a ratio of 17:1.
(KBr): nĈ 3467, 1634, 1568 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 1.96 ±
2.04 (m, 1H), 2.25 ± 2.33 (m, 1H), 2.48 (s, 3H), 2.85 (brs, 1H), 2.92 ± 2.98
(m, 1H), 3.03 ± 3.11 (m, 1H), 3.65 ± 3.70 (m, 1H), 3.83 (brd, 2H, J ˆ
6.5 Hz), 3.90 (s, 3H), 4.13 (s, 3H), 6.93 (s, 1H), 7.24 (s, 1H); 13C NMR
(126 MHz, CDCl3): d ˆ 23.7, 28.8, 31.4, 46.1, 53.6, 62.1, 66.1, 111.2, 112.7,
117.4, 134.9, 142.2, 148.4, 149.6, 153.2, 159.1; C16H19NO3: elemental analysis
calcd for C 70.31, H 7.01, N 5.12; found C 70.37, H 6.98, N 5.13.
8-Formyl-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopent[g]isoquino-
line (16): Under a nitrogen atmosphere, Dess ± Martin periodinane (4.8 g,
10.7 mmol) was added to an ice-cooled solution of 15 (2.9 g, 10.7 mmol) in
CH2Cl2 (120 mL). The reaction mixture was stirred at room temperature
for 30 min. Dess ± Martin periodinane (1.0 g, 2.3 mmol) was added, and the
whole mixture was stirred at room temperature for 20 min and poured into
saturated aqueous Na2S2O3. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2. The combined organic layer was
washed with aqueous saturated NaHCO3, dried (Na2SO4), and concen-
trated in vacuo to give 16 (2.8 g). This product was used for the following
reaction without prior purification. Analytically pure sample was obtained
by recrystallization from hexane/EtOAc. M.p. 103 ± 1048C; IR (KBr): nĈ
Major diastereomer (less polar isomer); a pale yellowgum. IR (KBr): nĈ
1727, 1715, 1628, 1613 cmÀ1; 1H NMR (270 MHz, CDCl3): d ˆ 2.19 (s, 3H),
2.45 (s, 3H), 2.58 (ddd, 1H, J ˆ 14.0, 9.0, 7.0 Hz), 2.85 (ddd, 1H, J ˆ 14.0,
9.5, 5.0 Hz), 3.15 (ddd, 1H, J ˆ 14.5, 9.0, 5.0 Hz), 3.32 (ddd, 1H, J ˆ 14.5,
9.5, 7.0 Hz), 3.56 (s, 3H), 3.73 (s, 3H), 3.83 (s, 3H), 4.05 (s, 3H), 4.91 (ABq,
1H, J ˆ 12.5 Hz), 4.97 (ABq, 1H, J ˆ 12.5 Hz), 6.35 (s, 1H), 6.71 (s, 1H),
6.78 (s, 1H), 6.85 (s, 1H), 7.13 ± 7.21 (m, 2H), 7.23 ± 7.35 (m, 7H), 7.40 ± 7.46
(m, 2H); 13C NMR (75 MHz, CDCl3): d ˆ 23.7, 26.3, 31.8, 32.2, 53.6, 55.9,
56.0, 63.2, 67.9, 68.2, 72.2, 73.0, 96.3, 100.2, 111.1, 111.3, 112.5, 113.4, 117.0,
126.2, 126.4, 127.1, 127.8, 128.5, 129.2, 131.6, 132.5, 136.8, 142.7, 143.2, 149.3,
149.7, 153.2, 154.5, 154.7, 159.1, 163.7, 205.8; HRMS (FAB): anal. calcd for
1725, 1634, 1568 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 2.25 ± 2.47 (m,
2H), 2.50 (s, 3H), 3.05 ± 3.13 (m, 2H), 3.85 (s, 3H), 4.14 (s, 3H), 4.15 ± 4.21
(m, 1H), 6.96 (s, 1H), 7.29 (s, 1H), 9.75 (d, 1H, J ˆ 3.0 Hz); 13C NMR
(75 MHz, CDCl3): d ˆ 23.8, 26.1, 32.2, 53.7, 55.4, 61.9, 111.2, 112.8, 117.4,
130.2, 142.8, 148.9, 149.0, 153.7, 159.2, 199.6; HRMS (FAB): anal. calcd for
‡
C42H40NO8S: 718.2475 [M ‡ H] ; found 718.2500.
Minor diastereomer (more polar isomer); a pale yellowgum; IR (KBr):
nĈ 1723, 1713, 1626, 1611 cmÀ1
;
1H NMR (270 MHz, CDCl3): d ˆ 2.08 (s,
‡
C16H18NO3: 272.1287 [M ‡ H] ; found 272.1295.
3H), 2.28 (ddd, 1H, J ˆ 14.5, 8.5, 7.0 Hz), 2.49 (s, 3H), 2.65 (ddd, 1H, J ˆ
14.5, 9.0, 8.0 Hz), 3.03 ± 3.14 (m, 2H), 3.84 (s, 3H), 3.88 (s, 3H), 3.96 (s, 3H),
4.11 (s, 3H), 5.12 (ABq, 1H, J ˆ 12.0 Hz), 5.13 (ABq, 1H, J ˆ 12.0 Hz), 6.51
(s, 1H), 6.83 ± 6.89 (m, 2H), 6.95 (s, 1H), 6.96 ± 7.13 (m, 4H), 7.20 ± 7.39 (m,
4H), 7.42 ± 7.39 (m, 2H), 7.50 (s, 1H); 13C NMR (68 MHz, CDCl3): d ˆ 23.7,
26.0, 30.9, 32.0, 53.7, 56.0, 56.3, 63.5, 67.0, 68.2, 72.2, 73.6, 95.3, 99.7, 111.0,
111.4, 112.7, 114.8, 117.3, 126.1, 126.4, 127.9, 128.0, 128.6, 128.9, 131.7, 132.1,
136.8, 143.0, 143.4, 149.4, 149.5, 153.6, 154.7, 155.0, 159.2, 164.8, 204.9;
elemental analysis calcd for C42H39NO8S: C 70.28, H 5.48, N 1.95, S 4.47;
found C 70.07, H 5.52, N 1.91, S 4.40.
Hydrazone (17): Under a nitrogen atmosphere, a solution of the above
crude 16 (2.8 g) and (R)-1-amino-2-(methoxymethyl)pyrrolidine (1.8 mL,
13 mmol) in CH2Cl2 (180 mL) was stirred at room temperature for 2 h. The
reaction mixture was concentrated in vacuo, and the residue was
immediately purified by flash column chromatography (hexane/EtOAc
5:1 ! 4:1) to give 17 (a 1:1 mixture of two diastereomers, 3.6 g, 87%) as a
yellowoil. Due to instability of this product, it was used for the following
reaction immediately. IR (KBr): nĈ 1630, 1615 cmÀ1; 1H NMR (500 MHz,
CDCl3): d ˆ 1.77 ± 1.97 (m, 4H), 2.22 ± 2.35 (m, 2H), 2.48 (s, 3H), 2.74 ± 2.80
(m, 1H), 2.93 ± 2.96 (m, 1H), 3.05 ± 3.10 (m, 1H), 3.30 ± 3.34 (m, 1H), 3.38
(s, 3H), 3.34 ± 3.46 (m, 2H), 3.61 ± 3.64 (m, 1H), 3.81 (s, 3/2H), 3.82 (s, 3/
2H), 4.110 (s, 3/2H), 4.112 (s, 3/2H), 4.18 ± 4.22 (m, 1H), 6.75 (d, 1/2H, J ˆ
6.5 Hz), 6.79 (d, 1/2H, J ˆ 6.5 Hz), 6.92 (s, 1H), 7.23 (s, 1H); HRMS: anal.
calcd for C22H29N3O3: 383.2209; found 383.2209.
8-[3-(2-Benzyloxy-4,5-dimethoxyphenyl)-1,3-dioxoprop-1-yl]-8-(1-hy-
droxy-3-phenylthio-2-propyn-1-yl)-1,9-dimethoxy-3-methyl-6,7-dihydro-
8H-cyclopent[g]isoquinoline (24): Under
a
nitrogen atmosphere,
LiN(TMS)2 (1.0m solution in THF, 3.3 mL, 3.3 mmol) was added to a
solution of 23 (a 17:1 mixture of two diastereomers, 0.79 g, 1.1 mmol) in
anhydrous toluene (20 mL). The reaction mixture was stirred at room
temperature for 2.5 h, after which time the consumption of the major
isomer was confirmed by silica gel TLC analysis (CHCl3/MeOH 100:1).
Anhydrous HMPA (0.64 mL, 3.5 mmol) was added, and the reaction
mixture was stirred at room temperature for 30 min, after which time, the
consumption of the minor isomer was confirmed by TLC analysis, see
above. The reaction mixture was poured into saturated aqueous NH4Cl,
and the product was extracted with CH2Cl2 (2 Â ). The combined organic
layer was washed with brine, dried (Na2SO4), and concentrated in vacuo.
Purification of the residue by flash column chromatography (hexane/
Hydrazone (18): Under a nitrogen atmosphere, nBuLi (1.5m solution in
hexane, 7.3 mL, 11.2 mmol) was added to (iPr)2NH (1.57 mL, 11.2 mmol) at
08C, and the mixture was stirred at 08C for 20 min. Anhydrous THF
(30 mL) was added, and the resulting clear solution was cooled to À788C.
A solution of 17 (3.6 g, 9.3 mmol) in anhydrous THF (60 mL) was added to
this solution, and the reaction mixture was stirred at À788C for 1 h. Acetyl
chloride (0.66 mL, 9.3 mmol) was added, and the reaction mixture was
stirred at À788C for 1.5 h. Saturated aqueous NH4Cl was added, and the
product was extracted with CH2Cl2 (3 Â ). The combined organic layer was
washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification
of the residue by flash column chromatography (hexane/EtOAc 4:1) gave
18 (a 1:1 mixture of two diastereomers, 3.1 g, 77%) as a pale yellow oil. IR
(KBr): nĈ 1709, 1568 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 1.74 ± 1.91 (m,
4H), 2.232 (s, 3/2H), 2.234 (s, 3/2H), 2.24 ± 2.42 (m, 3/2H), 2.45 (s, 3H),
2.66 ± 2.69 (m, 1/2H), 2.76 ± 2.88 (m, 2H), 3.04 ± 3.14 (m, 2H), 3.28 (s, 3/
2H), 3.30 (s, 3/2H), 3.30 ± 3.38 (m, 2H), 3.47 ± 3.50 (m, 1H), 3.78 (s, 3/2H),
3.79 (s, 3/2H), 4.12 (s, 3H), 6.945 (s, 1/2H), 6.952 (s, 1/2H), 7.01 (s, 1/2H),
EtOAc 2:1) gave 24 (0.56 g, 70%) as
a separable mixture of two
diastereomers in a ratio of 17:1.
Major isomer (less polar isomer); a yellowgum; IR (KBr): nĈ 3600 ± 3300,
1713, 1626, 1615 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 2.34 ± 2.42 (m,
2H), 2.49 (s, 3H), 2.87 ± 3.04 (m, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 3.88 (s,
3H), 4.04 (s, 3H), 4.87 (ABq, 1H, J ˆ 11.5 Hz), 4.90 (ABq, 1H, J ˆ
11.5 Hz), 5.02 (ABq, 1H, J ˆ 9.5 Hz), 5.08 (ABq, 1H, J ˆ 9.5 Hz), 6.41 (s,
Chem. Eur. J. 2000, 6, No. 21
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0621-3903 $ 17.50+.50/0
3903

Y. Kita et al.
FULL PAPER
1H), 6.66 (s, 1H), 6.77 ± 6.86 (m, 3H), 6.80 (s, 1H), 6.93 (s, 1H), 6.89 ± 7.02
(m, 1H), 7.18 ± 7.24 (m, 3H), 7.32 ± 7.39 (m, 3H), 7.49 (s, 1H), 16.29 (s, 1H);
13C NMR (75 MHz, CDCl3): d ˆ 23.7, 30.6, 36.5, 53.6, 56.0, 56.3, 63.2, 67.8,
68.4, 71.3, 71.8, 98.3, 98.9, 99.6, 111.0, 111.9, 112.7, 114.9, 117.5, 125.6, 126.0,
127.5, 128.4, 128.7, 128.8, 132.1, 132.3, 136.1, 143.0, 143.4, 149.1, 150.1, 153.0,
153.8, 153.9, 159.1, 178.7, 198.6; HRMS (FAB): anal. calcd for C42H40NO8S:
(19 mg, 77 mmol) was added. The reactor was sealed and heated at 1008C
for 10 h. After cooling, the reaction mixture was transferred to a round
bottomed flask and concentrated in vacuo. The residue was dissolved in
anhydrous DMF (1 mL), Et3N (0.20 mL, 1.4 mmol) and tBu2Si(OTf)2
(0.25 mL, 0.69 mmol) were added. The reaction mixture was stirred at
room temperature overnight. Similar workup as described for the
preparation of 5a followed by purification by flash column chromatog-
raphy (hexane ! hexane/EtOAc 5:1) gave 8,9-[di(tert-butyl)silylenedioxy]-
1',5,6,9'-tetramethoxy-3'-methyl-4-phenylthio-6',7'-dihydrospiro[2H-benz-
[f]indene-2,8'-8'H-cyclopent[g]isoquinoline]-1,3-dione (9.0 mg) as a yellow
gum. This product was contaminated with small amounts of hardly
separable impurities and used for the following reaction without further
‡
718.2474 [M ‡ H] ; found 718.2474.
Minor isomer (more polar isomer); a yellowgum; IR (KBr): nĈ 3600 ±
3300, 1713, 1626, 1611 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 2.33 (ddd,
1H, J ˆ 14.5, 9.0, 5.0 Hz), 2.45 (s, 3H), 2.83 (ddd, 1H, J ˆ 16.5, 9.0, 6.0 Hz),
2.95 (ddd, 1H, J ˆ 14.5, 9.0, 6.0 Hz), 3.09 (ddd, 1H, ddd, J ˆ 16.5, 9.0,
5.0 Hz), 3.75 (s, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 4.05 (s, 3H), 4.16 ( d, 1H,J ˆ
3.0 Hz), 4.76 (ABq, 1H, J ˆ 12.0 Hz), 4.80 (ABq, 1H, J ˆ 12.0 Hz), 5.96 (d,
1H, J ˆ 3.0 Hz), 6.32 (s, 1H), 6.35 (s, 1H), 6.76 ± 6.82 (m, 2H), 6.86 ± 6.96
(m, 3H), 6.99 ± 7.10 (m, 3H), 7.12 (s, 1H), 7.18 ± 7.35 (m, 3H), 7.40 (s, 1H),
15.64 (s, 1H); 13C NMR (75 MHz, CDCl3): d ˆ 23.7, 31.6, 32.6, 53.6, 55.9,
56.3, 62.7, 65.9, 66.5, 71.2, 71.6, 96.9, 98.5, 99.8, 111.4, 111.6, 112.8, 114.0,
117.0, 125.6, 125.9, 126.1, 127.3, 128.3, 128.8, 132.3, 134.5, 136.1, 143.1, 143.2,
148.9, 149.8, 152.8, 153.5, 154.3, 159.1, 175.1, 206.3; HRMS (FAB): anal.
purification. IR (KBr): nĈ 1736, 1703, 1630, 1603 cmÀ1
;
1H NMR
(500 MHz, CDCl3): d ˆ 1.11 (s, 9H), 1.12 (s, 9H), 1.93 ± 2.02 (m, 1H),
2.31 ± 2.38 (m, 1H), 2.45 (s, 3H), 3.07 ± 3.16 (m, 1H), 3.18 ± 3.25 (m, 1H),
3.43 (s, 3H), 3.94 (s, 3H), 4.00 (s, 3H), 4.02 (s, 3H), 6.90 (s, 1H), 6.93 ± 6.98
(m, 1H), 6.95 (s, 1H), 7.09 (t, 2H, J ˆ 7.5 Hz), 7.15 (d, 2H, J ˆ 7.5 Hz), 7.20
‡
(s, 1H); HRMS (FAB): anal. calcd for C43H46NO8SSi: 764.2713 [M ‡ H] ;
found 764.2716.
‡
calcd for C42H40NO8S: 718.2474 [M ‡ H] ; found 718.2468.
mCPBA (80% purity, 2.8 mg, 13 mmol) was added to a solution of the
above product (9.0 mg) in CH2Cl2 (1.5 mL) at À708C. The reaction mixture
was stirred at À708C for 1.5 h, and gradually warmed to À508C over a
period of 30 min. Saturated aqueous Na2S2O3 was added and purified
further as described above for the preparation of 5a; compound 26 (6.9 mg,
47% from 25) was obtained as a separable 1:1 mixture of two diaster-
eomers.
{8-[3-(2-Hydroxy-4,5-dimethoxyphenyl)-1,3-dioxoprop-1-yl]-8-(1-oxo-3-
phenylthio-2-propyn-1-yl)-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclo-
pent[g]isoquinoline}hexacarbonyldicobalt (25): Dess ± Martin periodinane
(34 mg, 80 mmol) was added to a solution of 24 (a 17:1 mixture of two
diastereomers, 38 mg, 53 mmol) in CH2Cl2 (2.0 mL). The reaction mixture
was stirred at room temperature for 1 h and poured into saturated aqueous
Na2S2O3. The same workup as described for the preparation of 10 from 13
Less polar isomer; a pale yellowgum; IR (KBr): nĈ 1740, 1709, 1629,
gave
oxo-3-phenylthio-2-propyn-1-yl)-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-
cyclopent[g]isoquinoline (34 mg) as pale yellowgum. Due to its
8-[3-(2-benzyloxy-4,5-dimethoxyphenyl)-1,3-dioxoprop-1-yl]-8-(1-
1605 cmÀ1
;
1H NMR (270 MHz, CDCl3): d ˆ 1.16 (s, 9H), 1.18 (s, 9H),
2.32 ± 2.60 (m, 2H), 2.46 (s, 3H), 3.22 ± 3.43 (m, 2H), 3.52 (brs, 3H), 3.54 (s,
3H), 4.00 (s, 3H), 4.01 (s, 3H), 6.93 (s, 1H), 6.96 (s, 1H), 7.26 (s, 1H), 7.34 ±
7.44 (m, 3H), 7.74 (d, 2H, J ˆ 7.5 Hz); 13C NMR (68 MHz, CDCl3): d ˆ 21.1,
21.2, 23.7, 25.9, 26.0, 32.2, 35.9, 53.4, 56.3, 60.6, 62.8, 65.8, 103.9, 111.0, 112.9,
113.5, 117.0, 125.5, 128.3, 129.0, 134.0, 139.8, 143.2, 148.6, 149.8, 151.2, 152.7,
154.6, 155.5, 158.9, 197.6.
a
instability, the product was used without further purification. IR (KBr):
nĈ 2122, 1732, 1661, 1626, 1615 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 2.45
(s, 3H), 2.65 ± 2.86 (m, 2H), 2.95 ± 3.05 (m, 2H), 3.74 (s, 3H), 3.83 (s, 3H),
3.85 (s, 3H), 3.92 (s, 3H), 4.93 (ABq, 1H, J ˆ 12.5 Hz), 5.04 (ABq, 1H, J ˆ
12.5 Hz), 6.35 (s, 1H), 6.93 (s, 1H), 6.95 (s, 1H), 7.05 ± 7.43 (m, 11H), 7.48 (s,
1H), 16.31 (s, 1H); 13C NMR (75 MHz, CDCl3): d ˆ 23.7, 31.5, 37.9, 53.3,
55.8, 56.2, 60.4, 62.8, 71.0, 73.4, 98.4, 100.6, 101.4, 111.4, 111.7, 112.7, 114.8,
116.8, 126.5, 127.1, 127.4, 127.9, 128.6, 129.4, 129.9, 133.2, 136.3, 143.1, 143.3,
148.6, 149.1, 152.9, 153.8, 154.6, 159.1, 178.4, 183.7, 195.0; HRMS (FAB):
More polar isomer; a pale yellowgum; IR (KBr): nĈ 1742, 1709, 1630,
1605 cmÀ1; 1H NMR (270 MHz, CDCl3): d ˆ 1.15 (s, 9H), 1.17 (s, 9H), 2.43
(s, 3H), 2.50 ± 2.67 (m, 2H), 3.10 (s, 3H), 3.25 ± 3.40 (m, 2H), 3.81 (brs, 3H),
3.97 (s, 3H), 4.05 (s, 3H), 6.90 (s, 1H), 6.99 (s, 1H), 7.22 (s, 1H), 7.28 (t, 1H,
J ˆ 7.5 Hz), 7.36 (d, 2H, J ˆ 7.5 Hz), 7.60 (d, 2H, J ˆ 7.5 Hz); 13C NMR
(68 MHz, CDCl3): d ˆ 20.8, 21.4, 23.6, 26.0, 31.5, 32.3, 36.0, 53.3, 56.2, 61.1,
61.9, 65.7, 103.3, 110.8, 112.8, 116.6, 116.9, 125.9, 128.0, 128.1, 128.9, 133.8,
138.5, 142.9, 144.7, 148.2, 149.8, 150.9, 152.1, 154.1, 155.0, 158.5, 197.4;
‡
anal. calcd for C42H38NO8S: 716.2318 [M ‡ H] ; found 716.2385.
Similarly to the preparation of 34, the above product (34 mg) was stirred
with Co2(CO)8 (37 mg, 0.12 mmol), and the product was purified by flash
column chromatography (hexane/EtOAc 3:1) to give {8-[3-(2-benzyloxy-
4,5-dimethoxyphenyl)-1,3-dioxoprop-1-yl]-8-(1-oxo-3-phenylthio-2-pro-
pyn-1-yl)-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopent[g]isoquinoli-
ne}hexacarbonyldicobalt (45 mg, 84% from 24) as a dark green gum. IR
‡
HRMS (FAB): anal. calcd for C43H46NO9SSi: 780.2663 [M ‡ H] ; found
780.2665.
4-Chloroacetoxy-8,9-[di(tert-butyl)silylenedioxy]-1',5,6,9'-tetramethoxy-
3'-methyl-6',7'-dihydrospiro[2H-benz[f]indene-2,8'-8'H-cyclopent[g]iso-
quinoline]-1,3-dione (27): Similarly to the preparation of 8a, 26 (46 mg,
60 mmol) was heated with anhydrous p-toluenesulfonic acid (1.0 mg,
6 mmol) and 7b (0.039 mL, 25 mmol) in anhydrous toluene (2.0 mL) at
1208C for 20 min. Similar workup and the purification by flash column
chromatography (hexane/EtOAc 5:1) gave 27 (35 mg, 77%) as a pale
(KBr): nĈ 2097, 2062, 2035, 1727, 1661, 1628, 1615 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d ˆ 2.46 (s, 3H), 2.58 ± 2.79 (m, 2H), 2.86 ± 2.95 (m,
2H), 3.78 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H), 3.98 (s, 3H), 4.86 (ABq, 1H,
J ˆ 12.0 Hz), 4.92 (ABq, 1H, J ˆ 12.0 Hz), 6.40 (s, 1H), 6.72 (s, 1H), 6.91 (s,
1H), 7.12 ± 7.56 (m, 12H), 16.29 (s, 1H).
Under an argon atmosphere, BCl3 (1.0m in CH2Cl2, 0.010 mL, 10 mmol) was
added to an ice-cooled solution of the above product (9.5 mg, 9.4 mmol) in
anhydrous CH2Cl2 (3.0 mL). The reaction mixture was stirred at 08C for 1 h
and poured into ice-water. The same workup as described for the
preparation of 34 and the purification by preparative TLC (hexane/EtOAc
2:1) gave 25 (3.2 mg, 37%) as a 3:1 mixture of keto- and enol-forms as a
yellowgum. IR (KBr): nĈ 1792, 1736, 1707, 1630, 1605 cmÀ1
;
1H NMR
(500 MHz, CDCl3): d ˆ 1.13 (s, 9H), 1.17 (s, 9H), 2.47 (s, 3H), 2.48 ± 2.59
(m, 2H), 3.31 ± 3.58 (m, 2H), 3.52 (brs, 3H), 3.75 (s, 3H), 4.02 (s, 3H), 4.03
(s, 3H), 4.46 (ABq, 1H, J ˆ 15.5 Hz), 4.51 (ABq, 1H, J ˆ 15.5 Hz), 6.96 (s,
2H), 7.31 (s, 1H); 13C NMR (68 MHz, CDCl3): d ˆ 21.1, 21.2, 23.7, 26.0, 26.1,
31.6, 32.4, 40.7, 53.5, 56.5, 62.1, 62.5, 66.1, 104.3, 119.3, 111.0, 113.0, 115.0,
117.3, 127.0, 127.1, 127.5, 138.9, 143.3, 148.7, 148.8, 149.7, 149.9, 151.4, 154.8,
158.8, 165.9, 198.1, 205.8; HRMS (FAB): anal. calcd for C39H43ClNO10Si:
dark green gum. IR (KBr): nĈ 2099, 2064, 2039, 1717, 1628, 1615 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 2.49 (s, 3H), 2.76 ± 2.98 (m, 2H), 3.03 ±
3.25 (m, 2H), 3.62 (s, 3/4H), 3.78 (s, 9/4H), 3.86 (s, 3/4H), 3.89 (s, 3/4H),
3.90 (s, 9/4H), 3.95 (s, 9/4H), 4.04 (s, 9/4H), 4.05 (s, 3/4H), 4.27 (ABq, 3/4H,
J ˆ 16.0 Hz), 4.51 (ABq, 3/4H, J ˆ 16.0 Hz), 6.27 (s, 1/4H), 6.40 (s, 3/4H),
6.71 (s, 1/4H), 6.96 (s, 3/4H), 6.97 (s, 1/4H), 7.26 ± 7.48 (m, 25/4H), 7.57 (s, 3/
4H), 12.02 (s, 1/4H), 12.39 (s, 1/4H), 15.60 (s, 3/4H).
‡
748.2344 [M ‡ H] ; found 748.2344.
4-Chloroacetoxy-8,9-[di(tert-butyl)silylenedioxy]-5,6,9'-trimethoxy-3'-
methyl-6',7'-dihydrospiro[2H-benz[f]indene-2,8'-8'H-cyclopent[g]isoquin-
oline]-1,1'(2'H),3-trione (28): Under a nitrogen atmosphere, Et3N (51 mL,
0.37 mmol), tBu2Si(OTf)2 (68 mL, 0.19 mmol), and MeI (12 mL, 57 mmol)
were added successively to a solution of 27 (14 mg, 19 mmol) in anhydrous
DMF (1.0 mL). The reaction mixture was stirred at room temperature for
4 h and poured into water. The product was extracted with EtOAc (2 Â ),
and the combined organic layer was washed with brine, dried (Na2SO4), and
concentrated in vacuo. Purification of the residue by flash column
chromatography (hexane/EtOAc 1:2) gave 28 (14 mg, quant.) as a pale
8,9-[Di(tert-butyl)silylenedioxy]-1',5,6,9'-tetramethoxy-3'-methyl-4-phen-
ylsulfinyl-6',7'-dihydrospiro[2H-benz[f]indene-2,8'-8'H-cyclopent[g]iso-
quinoline]-1,3-dione (26): Under
a nitrogen atmosphere, 25 (18 mg,
19 mmol) and anhydrous toluene (2.0 mL) were placed in a glass reactor,
Et3N (22 mL, 0.16 mmol) and Me2SiCl2 (10 mL, 78 mmol) were added. The
reaction mixture was stirred at room temperature for 30 min, and chloranil
3904
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Chem. Eur. J. 2000, 6, No. 21

(Æ)-Fredericamycin A
3897±3905
yellowgum. IR (KBr): nĈ 1790, 1736, 1707, 1646, 1619, 1605 cmÀ1; 1H NMR
(500 MHz, CDCl3): d ˆ 1.13 (s, 9H), 1.16 (s, 9H), 2.26 (s, 3H), 2.47 ± 2.59
(m, 2H), 3.26 ± 3.41 (m, 2H), 3.59 (brs, 3H), 3.89 (s, 3H), 4.01 (s, 3H), 4.46
(ABq, 1H, J ˆ 15.0 Hz), 4.51 (ABq, 1H, J ˆ 15.0 Hz), 6.17 (s, 1H), 6.94 (s,
1H), 7.10 (s, 1H), 9.28 (brs, 1H); HRMS (FAB): anal. calcd for
[1] Isolation and structure elucidation: a) R. C. Pandey, M. W. Toussaint,
R. M. Stroshane, C. C. Kalita, A. A. Aszalos, A. L. Garretson, T. T.
Wei, K. M. Byrne, R. F. Geoghegan, Jr., R. J. White, J. Antibiot. 1981,
34, 1389 ± 1401; b) R. Misra, R. C. Pandey, B. D. Hilton, P. P. Roller,
J. V. Silverton, J. Antibiot. 1987, 40, 786 ± 802. Biological activity:
c) D. J. Warnick-Pickle, K. M. Byrne, R. C. Pandey, R. J. White, J.
Antibiot. 1981, 34, 1402 ± 1407; d) M. D. Latham, C. K. King, P.
Gorycki, T. L. Macdonald, W. E. Ross, Cancer Chemother. Pharmacol.
1989, 24, 167 ± 171.
[2] T. R. Kelly, S. H. Bell, N. Ohashi, R. J. Armstrong-Chong, J. Am.
Chem. Soc. 1988, 110, 6471 ± 6480.
[3] D. L. J. Clive, Y. Tao, A. Khodabocus, Y.-J. Wu, A. G. Angoh, S. M.
Bennett, C. N. Boddy, L. Bordeleau, D. Kellner, G. Kleiner, D. S.
Middleton, C. J. Nichols, S. R. Richardson, P. G. Vernon, J. Am. Chem.
Soc. 1994, 116, 11275 ± 11286.
‡
C38H41ClNO10Si: 734.2188 [M ‡ H] ; found 734.2195.
4-Chloroacetoxy-8,9-[di(tert-butyl)silylenedioxy]-3'-formyl-5,6,9'-tri-
methoxy-6',7'-dihydrospiro[2H-benz[f]indene-2,8'-8'H-cyclopent[g]iso-
quinoline]-1,1'(2'H),3-trione (29): Under a nitrogen atmosphere, a mixture
of 28 (14 mg, 19 mmol) and SeO2 (8.3 mg, 75 mmol) in anhydrous dioxane
(1.0 mL) was stirred under reflux for 1 h. After cooling, the reaction
mixture was filtered through a Celite pad, and the filtrate was concentrated
in vacuo. Purification of the residue by flash column chromatography
(hexane/EtOAc 1:1) gave 29 (11 mg, 78%) as a pale yellowgum. IR (KBr):
nĈ 1788, 1734, 1707, 1682, 1607 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 1.13
(s, 9H), 1.17 (s, 9H), 2.53 ± 2.65 (m, 2H), 3.34 ± 3.47 (m, 2H), 3.62 (brs, 3H),
3.89 (s, 3H), 4.02 (s, 3H), 4.46 (ABq, 1H, J ˆ 15.5 Hz), 4.51 (ABq, 1H, J ˆ
15.5 Hz), 6.96 (s, 1H), 7.03 (s, 1H), 7.41 (s, 1H), 8.68 (brs, 1H), 9.53 (s, 1H);
[4] A. V. Rama Rao, A. K. Singh, B. V. Rao, K. M. Reddy, Heterocycles
1994, 37, 1893 ± 1912.
[5] L. Saint-Jalmes, C. Lila, J. Z. Xu, L. Moreau, B. Pfeiffer, G. Eck, L.
Pelsez, C. Rolando, M. Julia, Bull. Soc. Chim. Fr. 1993, 130, 447 ± 449.
[6] J. A. Wendt, P. J. Gauvreau, R. D. Bach, J. Am. Chem. Soc. 1994, 116,
9921 ± 9926.
‡
HRMS (FAB): anal. calcd for C38H39ClNO11Si: 748.1981 [M ‡ H] ; found
748.1962.
4-Chloroacetoxy-8,9-[di(tert-butyl)silylenedioxy]-5,6,9'-trimethoxy-3'-(1,3-
pentadienyl)-6',7'-dihydrospiro[2H-benz[f]indene-2,8'-8'H-cyclopent[g]-
isoquinoline]-1,1'(2'H),3-trione (30): Under a nitrogen atmosphere, nBuLi
(1.5m solution in hexane, 0.17 mL, 0.25 mmol) was added to an ice-cooled
suspension of crotyltriphenylphosphonium bromide (0.10 g, 0.25 mmol) in
anhydrous THF (4 mL), and the reaction mixture was stirred at 08C for 1 h.
The supernatant (0.26 mL) of this mixture was added to a solution of 29
(9.4 mg, 13 mmol) in anhydrous THF (1 mL) at À788C. The reaction
mixture was stirred at À788C for 30 min, warmed to room temperature,
stirred at room temperature for 2 h, and poured into a solution of saturated
aqueous NH4Cl solution. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2. The combined organic layer was washed
with brine, dried (Na2SO4), and concentrated in vacuo. Purification of the
residue by preparative TLC (hexane/EtOAc 2:3) gave 30 (a 5:1 mixture of
E,E- and E,Z-isomers, 2.8 mg, 28%) and unreacted 29 (6.3 mg, 67%). 30:
pale yellowgum; IR (KBr): nĈ 1790, 1738, 1709, 1646, 1607 cmÀ1; 1H NMR
(500 MHz, CDCl3): d ˆ 1.13 (s, 9H), 1.16 (s, 9H), 1.84 (d, 5/2H, J ˆ 7.0 Hz),
1.86 (dd, 1/2H, J ˆ 7.0, 1.5 Hz), 2.48 ± 2.61 (m, 2H), 3.27 ± 3.42 (m, 2H), 3.60
(brs, 5/2H), 3.61 (brs, 1/2H), 3.85 (s, 3H), 4.02 (s, 3H), 4.46 (ABq, 1H, J ˆ
15.5 Hz), 4.51 (ABq, 1H, J ˆ 15.5 Hz), 5.75 (dq, 1/6H, J ˆ 10.5, 7.0 Hz), 5.93
(dq, 5/6H, J ˆ 15.0, 7.0 Hz), 6.08 (d, 5/6H, J ˆ 16.0 Hz), 6.13 ± 6.22 (m, 1H),
6.18 (d, 1/6H, J ˆ 16.0 Hz), 6.29 (s, 5/6H), 6.34 (s, 1/6H), 6.53 (dd, 5/6H, J ˆ
16.0, 10.5 Hz), 6.87 (dd, 1/6H, J ˆ 16.0, 10.5 Hz), 6.94 (s, 1H), 7.15 (s, 5/6H),
7.17 (s, 1/6H), 8.33 (brs, 5/6H), 8.46 (brs, 1/6H); HRMS (FAB): anal. calcd
[7] D. L. Boger, O. Hüter, K. Mbiya, M. Zhang, J. Am. Chem. Soc. 1995,
117, 11839 ± 11849.
[8] a) Y. Kita, K. Higuchi, Y. Yoshida, K. Iio, S. Kitagaki, S. Akai, H.
Fujioka, Angew. Chem. 1999, 111, 731 ± 734; Angew. Chem. Int. Ed.
1999, 38, 683 ± 686; for a review, see: b) Y. Kita, S. Akai, H. Fujioka, J.
Synth. Org. Chem. Jpn. 1998, 56, 963 ± 974 [Chem. Abstr. 1998, 129,
343342].
[9] The strong base induced intermolecular [4 ‡ 2] cycloaddition of
homophthalic anhydrides, see: a) Y. Tamura, M. Sasho, K. Nakagawa,
T. Tsugoshi, Y. Kita, J. Org. Chem. 1984, 49, 473 ± 478; b) Y. Tamura,
Y. Kita, J. Synth. Org. Chem. Jpn. 1988, 46, 205 ± 217 [Chem. Abstr.
1988, 109, 129465d]; c) Y. Kita, K. Iio, A. Okajima, Y. Takeda, K.
Kawaguchi, B. A. Whelan, S. Akai, Synlett 1998, 292 ± 294; d) K. Iio,
N. G. Ramesh, A. Okajima, K. Higuchi, H. Fujioka, S. Akai, Y. Kita, J.
Org. Chem. 2000, 65, 89 ± 95.
[10] For reviews, see: a) A. G. Fallis, Can. J. Chem. 1984, 62, 183 ± 234;
b) E. J. Thomas, Acc. Chem. Res. 1991, 24, 229 ± 235.
[11] For preparation of 1-ethoxyvinyl esters, see: Y. Kita, H. Maeda, K.
Omori, T. Okuno, Y. Tamura, J. Chem. Soc. Perkin Trans. 1 1993,
2999 ± 3005.
[12] Recently, we have reported that 1-ethoxyvinyl esters were, in some
cases, superior to acid anhydrides, the most common reagents for the
Pummerer reactions.[12a] Examples involve asymmetric Pummerer
rearangements of optically active sulfoxides[12b,c] and isolation of the p-
quinone mono O,S-acetal intermediates of the aromatic Pummerer-
type rearrangement of p-sulfinylphenols.[13] See: a) O. D. Lucchi, U.
Miotti, G. Modena, Organic Reactions, Vol. 40 , Wiley, NewYork, 1991,
chapter 3; b) Y. Kita, N. Shibata, Synlett 1996, 289 ± 296; c) N. Shibata,
M. Matsugi, N. Kawano, S. Fukui, C. Fujimori, K. Gotanda, K.
Murata, Y. Kita, Tetrahedron: Asymmetry 1997, 8, 303 ± 310.
[13] Y. Kita, Y. Takeda, M. Matsugi, K. Iio, K. Gotanda, K. Murata, S.
Akai, Angew. Chem. 1997, 109, 1525 ± 1527; Angew. Chem. Int. Ed.
Engl. 1997, 36, 1529 ± 1531.
[14] M. Toyota, S. Terashima, Terahedron Lett. 1989, 30, 829 ± 832.
[15] Y. Kita, R. Okunaka, T. Honda, M. Kondo, O. Tamura, Y. Tamura,
Chem. Pharm. Bull. 1991, 39, 2106 ± 2114.
[16] a) S. Akai, K. Iio, Y. Takeda, H. Ueno, Y. Kita, Synlett 1997, 310 ± 312.
See also, b) Y. Kita, Y. Takeda, K. Iio, K. Yokogawa, K. Takahashi, S.
Akai, Tetrahedron Lett. 1996, 37, 7545 ± 7548; c) S. Akai, Y. Takeda, K.
Iio, K. Takahashi, N. Fukuda, Y. Kita, J. Org. Chem. 1997, 62, 5526 ±
5536.
‡
for C42H45ClNO10Si: 786.2501 [M ‡ H] ; found 786.2491.
(Æ)-Fredericamycin A (1): Under a nitrogen atmosphere, BBr3 (1.0m
solution in CH2Cl2, 0.10 mL, 0.10 mmol) was added to a solution of 30
(2.4 mg, 3.0 mmol) in anhydrous CH2Cl2 (1.0 mL) at À788C. The reaction
mixture was stirred at À788C for 1 h and gradually warmed to room
temperature over a period of 1 h. Water (1.0 mL) and THF (5.0 mL) were
added, and the reaction mixture was stirred in the air at room temperature
for 18 h. The product was extracted with CH2Cl2 twice, and the combined
organic layer was successively washed with saturated aqueous NaHCO3
and brine, dried (Na2SO4), and concentrated in vacuo. Purification of the
residue by preparative TLC (CHCl3/MeOH/AcOH 90:10:1) gave a mixture
of 1 and its E,Z-isomer. Further purification of this mixture by HPLC
(JASCO Megapac SIL NH2 ± 10, CHCl3/MeOH/AcOH 800:200:1) gave 1
(1.0 mg, 52%) as a red solid. This product was identical (1H NMR, UV,
HPLC, TLC) with an authentic sample of natural fredericamycin A by
direct comparison.
Acknowledgement
[17] Y. Kita, H. Ueno, S. Kitagaki, K. Kobayashi, K. Iio, S. Akai, J. Chem.
Soc., Chem. Commun. 1994, 701 ± 702.
We would like to thank Dr. Hiroshi Hasegawa (SS Pharmaceutical Co.,
Ltd., Japan) for generously providing an authentic sample of fredericamy-
cin A. We are also grateful to Akiko Okajima and Seiko Morishita for their
technical assistance. This work was financially supported by the Special
Coordination Funds of the Science and Technology Agency of the Japanese
Government, Grants-in-Aid for Scientific Research from the Ministry of
Education, Science, and Culture, Japan, the Japan Research Foundation for
Optically Active Compounds, and the Research Foundation for Pharma-
ceutical Sciences, Japan.
[18] A. Herunsalee, M. Isobe, T. Goto, Tetrahedron 1991, 47, 3727 ± 3736;
P. A. Magriotis, J. T. Brown, Org. Synth. 1993, 72, 252 ± 263.
[19] F. Bohlmann, H.-J. Mannhardt, Chem. Ber. 1956, 89, 1307 ± 1315.
[20] D. L. J. Clive, M. Cantin, A. Khodabocus, X. Kong, Y. Tao, Tetrahe-
dron 1993, 49, 7917 ± 7930.
Received: May 16, 2000 [F2488]
Chem. Eur. J. 2000, 6, No. 21
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0947-6539/00/0621-3905 $ 17.50+.50/0
3905