Enantiodivergent synthesis of either enantiomer of ABCDE-ring analogue of antitumor antibiotic fredericamycin A via intramolecular [4 + 2] cycloaddition approach

Article abstract of DOI:10.1021/ol016696y

matrix presented An intramolecular enantiodivergent synthesis of both enantiomers of the ABCDE-ring analogue 22 of fredericamycin A is reported. Key steps involved an intramolecular [4 + 2] cycloaddition of 17 and an aromatic Pummerer-type reaction of 19.

Full text of DOI:10.1021/ol016696y

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4015-4018
Enantiodivergent Synthesis of Either
Enantiomer of ABCDE-Ring Analogue of
Antitumor Antibiotic Fredericamycin A
via Intramolecular [4 + 2] Cycloaddition
Approach
Shuji Akai, Toshiaki Tsujino, Nobuhisa Fukuda, Kiyosei Iio, Yoshifumi Takeda,
,†
Ken-ichi Kawaguchi, Tadaatsu Naka, Kazuhiro Higuchi, and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6, Yamadaoka,
Suita, Osaka 565-0871, Japan
kita@phs.osaka-u.ac.jp
Received September 5, 2001
ABSTRACT
An intramolecular enantiodivergent synthesis of both enantiomers of the ABCDE-ring analogue 22 of fredericamycin A is reported. Key steps
involve an intramolecular [4 + 2] cycloaddition of 17 and an aromatic Pummerer-type reaction of 19. A lipase-catalyzed enantioselective
desymmetrization of prochiral diol 2 using 1-ethoxyvinyl 2-furoate 3 led to the pivotal intermediate (R)-4.
Due to potent antitumor activity against a variety of in vivo
tumor models and negative mutagenicity in the Ames test,
an antibiotic, fredericamycin A (1), has drawn much attention
as a leading compound for developing novel types of
chemotherapeutic drugs for human cancers.1 1 consists of
two peri-hydroxy tricyclic aromatic moieties, connected
through a chiral, spiro, quaternary carbon center, and its
chirality arises from the presence of a single methoxy group
at the farthest position of the A-ring. Intensive efforts have
been made toward asymmetric total synthesis of 1, including
the total syntheses of racemic 1 by five research groups2-6
and the HPLC separation of a racemic intermediate of 1 using
a chiral column.7 Until recently, no one had succeeded in
(2) Kelly, T. R.; Bell, S. H.; Ohashi, N.; Armstrong-Chong, R. J. J. Am.
Chem. Soc. 1988, 110, 6471.
(3) Clive, D. L. J.; Tao, Y.; Khodabocus, A.; Wu, Y.-J.; Angoh, A. G.;
Bennett, S. M.; Boddy, C. N.; Bordeleau, L.; Kellner, D.; Kleiner, G.;
Middleton, D. S.; Nichols, C. J.; Richardson, S. R.; Vernon, P. G. J. Am.
Chem. Soc. 1994, 116, 11275.
(4) Rama Rao, A. V.; Singh, A. K.; Rao, B. V.; Reddy, K. M.
Heterocycles 1994, 37, 1893.
(5) Saint-Jalmes, L.; Lila, C.; Xu, J. Z.; Moreau, L.; Pfeiffer, B.;
Eck, G.; Pelsez, L.; Rolando, C.; Julia, M. Bull. Soc. Chim. Fr. 1993, 130,
447.
† Fax: (+81) 6-6879-8229.
(1) Isolation and structure elucidation: (a) Pandey, R. C.; Toussaint, M.
W.; Stroshane, R. M.; Kalita, C. C.; Aszalos, A. A.; Garretson, A. L.; Wei,
T. T.; Byrne, K. M.; Geoghegan, R. F., Jr.; White, R. J. J. Antibiot. 1981,
34, 1389. (b) Misra, R.; Pandy, R. C.; Silverton, J. V. J. Am. Chem. Soc.
1982, 104, 4478. Studies on biological activity: (c) Latham, M. D.; King,
C. K.; Gorycki, P.; Macdonald, T. L.; Ross, W. E. Cancer Chemother.
Pharmacol. 1989, 24, 167. (d) Dalal, N. S.; Shi, X. Biochemistry 1989, 28,
748.
(6) Wendt, J. A.; Gauvreau, P. J.; Bach, R. D. J. Am. Chem. Soc. 1994,
116, 9921.
10.1021/ol016696y CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/16/2001

the asymmetric total synthesis of either 1 or its analogue8
because of the lack of an efficient distinction of the enantio
face of the highly symmetrical AB-plane.9
active 1. In this Letter we report an application of this
intramolecular cycloaddition approach involving the inter-
mediates I-III to the asymmetric synthesis of the optically
active ABCDE-ring analogue 22. Either enantiomer (R)- or
(S)-22 was obtained from a single key intermediate, (R)-4,
with perfect retention of its chiral integrity.
Preparation of both enantiomers of the optically active keto
aldehyde, (R)- and (S)-10, corresponding to II, was the first
objective in this study. Creation of the chiral quaternary
carbon center was performed by the lipase-catalyzed desym-
metrization of prochiral diol 2 using 1-ethoxyvinyl 2-furoate
3.12 The desired (R)-4 (21% yield, 96% ee) was obtained
along with the diester 5 (78% yield), and 5 was recycled to
2 almost quantitatively. Silylation of (R)-4 followed by
saponification afforded the monosilyl ether (S)-6 (95% yield,
96% ee). Stepwise oxidation of (S)-6 by the Dess-Martin
periodinane and then by NaClO2 afforded the carboxylic acid
(R)-7 (88% yield), which was treated with BF3‚Et2O to give
(R)-8 (99% yield, 96% ee).13 Reaction of (R)-8 with MeLi
at 0 °C followed by quenching with aqueous NH4Cl solution
at -78 °C gave the keto-carbinol (R)-9 (80% yield, 96%
ee).13 The Dess-Martin oxidation of (R)-9 afforded (R)-10
(96% yield). A similar two-step oxidation of (R)-4 gave the
carboxylic acid (S)-11 (92% yield), which was then converted
to (S)-10 (49% yield, two steps) (Scheme 2).
We have planned two different asymmetric approaches for
1 through an optically pure quaternary carbon intermediate
with a definite stereochemistry at an early stage and the
completion of the total synthesis while retaining its chiral
integrity (Scheme 1). Accordingly, we have quite recently
Scheme 1
To prepare the key intermediate (S)-16, the installation of
the acetylene and the A-ring moieties to (R)-10 without loss
of its chiral integrity was troublesome. When the reaction
Scheme 2a
succeeded in the asymmetric total synthesis of natural 1 by
the intermolecular cycloaddition approach, and the absolute
stereochemistry of the natural product was determined for
the first time.10 Simultaneously, we have also achieved an
intramolecular total synthesis of racemic 1,10c,11 which is
believed to be useful for the asymmetric synthesis of optically
(7) Boger, D. L.; Hu¨ter, O.; Mbiya, K.; Zhang, M. J. Am. Chem. Soc.
1995, 117, 11839.
(8) Studies in this field are well summarized in ref 7. For recent synthetic
studies on the racemates, see: Baskaran, S.; Nagy, E.; Braun, M. Liebigs
Ann./Recl. 1997, 311. Clive, D. L. J.; Kong, X.; Paul, C. C. Tetrahedron
1996, 52, 6085. Evans, P. A.; Brandt, T. A. Tetrahedron Lett. 1996, 37,
1367. Perumal, P. T.; Venugopal, M.; Velusamy, T. P. Indian J. Chem.,
Sect. B 1996, 35B, 242.
(9) Quite a few methods applicable to asymmetric synthesis of 1 have
been developed, see: (a) Toyota, M.; Terashima, S. Terahedron Lett. 1989,
30, 829. (b) Trypke, W.; Steigel, A.; Braun, M. Synlett 1992, 827.
(10) (a) Kita, Y.; Higuchi, K.; Yoshida, Y.; Iio, K.; Kitagaki, S.; Akai,
S.; Fujioka, H. Angew. Chem., Int. Ed. 1999, 38, 683. (b) Kita, Y.; Higuchi,
K.; Yoshida, Y.; Iio, K.; Kitagaki, S.; Ueda, K.; Akai, S.; Fujioka, H. J.
Am. Chem. Soc. 2001, 123, 3214. (c) For a review, see: Kita, Y.; Akai, S.;
Fujioka, H. J. Synth. Org. Chem. Jpn. 1998, 56, 963.
a (a) 3, Candida rugosa lipase (Meito MY), iPr2O, 30 °C; (b)
K2CO3, MeOH; (c) 1. TBSCl, pyridine, DMF; 2. K2CO3, MeOH;
(d) 1. Dess-Martin periodinane, MeCN, 2. NaClO2, NaH2PO4,
2-methyl-2-butene, t-BuOH, H2O; (e) BF3‚Et2O, CH2Cl2; (f) MeLi,
HMPA, THF; (g) Dess-Martin periodinane, MeCN.
(11) Kita, Y.; Iio, K.; Kawaguchi, K.; Fukuda, N.; Takeda, Y.; Ueno,
H.; Okunaka, R.; Higuchi, K.; Tsujino, T.; Fujioka, H.; Akai, S. Chem.
Eur. J. 2000, 6, 3897.
4016
Org. Lett., Vol. 3, No. 25, 2001

Scheme 3a
Scheme 4a
a (a) 1. LiC≡CSPh, HMPA-THF, -78 °C; 2. 13, DMAP,
CH2Cl2; 3. LiN(TMS)2, THF; (b) 1. Moffatt oxidation; 2. Co2(CO)8,
CH2Cl2; 3. BCl3, CH2Cl2; (c) 1. Me2SiCl2, Et3N, chloranil, toluene,
100 °C; 2. (t-Bu)2Si(OTf)2, Et3N, DMF; (d) 1. m-CPBA, CH2Cl2;
2. 20, catalytic p-TsOH, toluene; 3. Bu4NF, THF-H2O; 4. BBr3,
CH2Cl2; 5. 80% aqueous CF3CO2H.
yield), which was subjected to intramolecular [4 + 2]
cycloaddition under the standard reaction conditions to afford
the pentacyclic product (S)-18 (47% yield). The optical purity
of (S)-18 was determined to be 96% ee by chiral HPLC
analysis, and the perfect retention of the chiral integrity of
(R)-4 was confirmed. Oxidation of (S)-18 to (S)-19 followed
by aromatic Pummerer-type reaction using 1-ethoxyvinyl
chloroacetate 20 in refluxing toluene15 introduced a hydroxyl
group to the B-ring. The crude product (R)-21 was subjected
to stepwise deprotection to afford the optically active
ABCDE-ring analogue (S)-22 having the same absolute
stereochemistry as natural 1 (Scheme 3).16
a (a) LiC≡CSPh, HMPA-THF, -78 °C; (b) 13, DMAP, CH2Cl2;
(c) LiN(TMS)2, THF; (d) Moffatt oxidation; (e) 1. Co2(CO)8,
CH2Cl2; 2. BCl3, CH2Cl2; (f) 1. Me2SiCl2, Et3N, chloranil, toluene,
100 °C; 2. (t-Bu)2Si(OTf)2, Et3N, DMF; (g) m-CPBA, CH2Cl2; (h)
20, catalytic p-TsOH, toluene; (i) 1. Bu4NF, THF-H2O; 2. BBr3,
CH2Cl2; 3. 80% aqueous CF3CO2H.
The same transformation was applied to (S)-10 (96% ee)
to provide the unnatural enantiomer (R)-22 [96% ee based
on the optical purity of (R)-18] (Scheme 4).16 A symmetrical
pair in the CD spectra of (S)- and (R)-22 was obtained
(12) Akai, S.; Naka, T.; Fujita, T.; Takebe Y.; Kita, Y. Chem. Commun.
2000, 1461.
(13) Special care was needed for the desilylation of (R)-7 and the reaction
of (R)-8 with MeLi, because a partial racemization of them was often
observed under basic conditions. For instance, the reaction of (R)-8 with
MeLi at 0 °C followed by quenching at the same temperature gave (R)-9
in e92% ee.
(14) The racemization may arise from a retro-aldol-aldol process of the
intermediate â-oxidoketone corresponding to 12. A similar reaction was
observed during a study of the asymmetric total synthesis of 1.10 A detailed
investigation about this racemization is now in progress and will be discussed
in the near future.
(15) (a) Kita, Y.; Takeda, Y.; Matsugi, M.; Iio, K.; Gotanda, K.; Murata
K.; Akai, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 1529. See also, (b)
Kita, Y.; Takeda, Y.; Iio, K.; Yokogawa, K.; Takahashi, K.; Akai, S.
Tetrahedron Lett. 1996, 37, 7545. (c) Akai, S.; Takeda, Y.; Iio, K.;
Takahashi, K.; Fukuda, N.; Kita, Y. J. Org. Chem. 1997, 62, 5526.
(16) Due to the poor solubility of 22 in various organic solvents and its
deep color, determination of its optical purity was difficult. All new
compounds were fully characterized by spectroscopic means and combustion
analysis.
of (R)-10 (96% ee) with lithium phenylthioacetylide was
carried out at room temperature, unexpected racemization
of the quaternary carbon center at the C-1 position was
brought about.14 This problem was overcome by running the
reaction at -78 °C and quenching at the same temperature
to give (1R)-12 (53% yield, 96% ee) as a single diastereomer.
Acylation of (1R)-12 with 13 gave (1R)-14 (96% yield),
which was treated with LiN(TMS)2 (3 equiv) in THF to
induce the migration of the A-ring aroyl moiety to the methyl
ketone terminus giving (1R)-15 (81% yield). Moffatt oxida-
tion of (1R)-15 afforded the trione (S)-16 (79% yield).
The following manipulation of (S)-16 was performed
similarly to the total synthesis of the racemate11 without any
problem. Thus, treatment of (S)-16 with Co2(CO)8 followed
by debenzylation provided the cobalt complex (S)-17 (50%
Org. Lett., Vol. 3, No. 25, 2001
4017

Acknowledgment. We are grateful to Akiko Okajima and
Seiko Morishita for their technical assistance. This work was
financially supported by Grants-in-Aid for Scientific Re-
search [Priority Areas (A) “Exploitation of Multi-Element
Cyclic Molecules” and No. 13672214] from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan,
and the Takeda Science Foundation, Japan. Meito Sangyo
Co., Ltd., Japan, is thanked for generous gift of lipase MY.
Supporting Information Available: 1H and 13C NMR
data of (S)-22 and racemic 23. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL016696Y
(17) The similarity of the 1H and 13C NMR data of (S)-22 with those of
racemic 23 [Boger, D. L.; Jacobson, I. C. J. Org. Chem. 1991, 56, 2115]
also supports its structure (In detail, see: Supporting Information).
Figure 1. CD spectra of (S)- and (R)-22.
(Figure 1). The spectroscopic data (IR, 1H NMR, 13C NMR,
HRMS) of (S)- and (R)-22 showed good agreement with its
structure.17
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Org. Lett., Vol. 3, No. 25, 2001