Enantioselective total synthesis of a potent antitumor antibiotic, fredericamycin A

Article abstract of DOI:10.1021/ja0035699

The asymmetric total synthesis of both enantiomers of the potent antitumor antibiotic fredericamycin A (1) is detailed based on the protocol for the construction of its peri-hydroxy polyaromatic skeleton bearing the chirality at the spiro carbon via a str

Full text of DOI:10.1021/ja0035699

3214
J. Am. Chem. Soc. 2001, 123, 3214-3222
Enantioselective Total Synthesis of a Potent Antitumor Antibiotic,
Fredericamycin A
Yasuyuki Kita,* Kazuhiro Higuchi, Yutaka Yoshida, Kiyosei Iio, Shinji Kitagaki,
Koichiro Ueda, Shuji Akai, and Hiromichi Fujioka
Contribution from the Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamada-oka,
Suita, Osaka 565-0871, Japan
ReceiVed October 2, 2000
Abstract: The asymmetric total synthesis of both enantiomers of the potent antitumor antibiotic fredericamycin
A (1) is detailed based on the protocol for the construction of its peri-hydroxy polyaromatic skeleton bearing
the chirality at the spiro carbon via a strong base-induced cycloaddition of suitably substituted homophthalic
anhydrides (AB-ring unit) with an optically active CDEF-ring unit. Particular attention has been given to the
novel synthesis of the optically active spiro carbon center by a stereospecific rearrangement of optically active
benzofuzed-trans-epoxy acylates leading to spirocyclopentane-1,1′-indane systems. This method is quite useful
for the construction of an optically active spiro compound and was applied to the synthesis of the optically
pure CDEF-ring unit of 1. Cycloaddition of the optically pure CDEF-ring unit to AB-ring units prepared via
benzyne afforded two natural and unnatural-type hexacyclic compounds, which were converted to natural and
unnatural enantiomers of synthetic 1, and the absolute configuration of natural 1 was determined as S.
Fredericamycin A (1), isolated from Streptomyces griseus in
which include six total syntheses: five in racemic form3-7 and
one in optically active form.8 Although the last synthesis by
Boger’s group achieved the synthesis of the optically active 1,
it requires an optical resolution of the racemic compound using
a chiral HPLC separation at the final stage of the synthesis.
Therefore the absolute configuration of 1 still remains unknown.
Most of the reported total syntheses and the related model
studies involve the construction of the spiro CD-ring in their
final stages, and the lack of an efficient method for the
enantiodifferentiation of the highly symmetrical AB-plane has
been the major obstacle in these asymmetric approaches
(Scheme 1).
We then planned to synthesize the optically active 1 and
determine the absolute configuration by a completely new
approach, which is also useful to synthesize its analogues.9
Scheme 2 shows our synthetic plan. Thus, the strong base-
induced intermolecular [4+2]-cyclocondensation10 of an opti-
cally active CDEF-ring unit and a suitably functionalized AB-
1981, exhibits potent antitumor activity against several tumor
models (in vivo) such as P388 leukemia, B16 melanoma, and
CD8F mammary carcinoma, and does not show mutagenicity
in the Ames test.1,2 Recent studies revealed that 1 inhibits both
topoisomerases I and II; however, little is known about the actual
mechanism of its action. In addition to these promising
biological profiles, its unique structure has attracted many
synthetic organic chemists. Compound 1 consists of two sets
of peri-hydroxy tricyclic aromatic moieties connected through
a spiro quaternary carbon center, whose chirality is determined
by the presence of a single methoxy group at the farthest position
on the A-ring.
(3) (a) Kelly, T. R.; Ohashi, N.; Armstrong-Chong, R. J.; Bell, S. H. J.
Am. Chem. Soc. 1986, 108, 7100-7101. (b) Kelly, T. R.; Bell, S. H.; Ohashi,
N.; Armstrong-Chong, R. J. J. Am. Chem. Soc. 1988, 110, 6471-6480.
(4) (a) 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. Chem.
Soc., Chem. Commun. 1992, 1489-1490. (b) 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-
11286.
(5) (a) Rama Rao, A. V.; Singh, A. K.; Rao, B. V.; Reddy, K. M.
Tetrahedron Lett. 1993, 34, 2665-2668. (b) Rama Rao, A. V.; Singh, A.
K.; Rao, B. V.; Reddy, K. M. Heterocycles 1994, 37, 1893-1912.
(6) 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-
449.
Numerous synthetic studies of 1 have been achieved so far,
(1) Isolation and structure elucidation; see: (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, 1389-1401. (b) Misra, R.; Pandey, R. C.; Silverton, J. V. J. Am.
Chem. Soc. 1982, 104, 4478-4479. (c) Byrne, K. M.; Hilton, B. D.; White,
R. J.; Misra, R.; Pandey, R. C. Biochemistry 1985, 24, 478-486. (d) Misra,
R.; Pandey, R. C.; Hilton, B. D.; Roller, P. P.; Silverton, J. V. J. Antibiot.
1987, 40, 786-802.
(2) Studies on biological activity; see: (a) Warnick-Pickle, D. J.; Byrne,
K. M.; Pandey, R. C.; White, R. J. J. Antibiot. 1981, 34, 1402-1407. (b)
Hilton, B. D.; Misra, R.; Zweier, J. L. Biochemistry 1986, 25, 5533-5539.
(c) Misra, R. J. Antibiot. 1988, 41, 976-981. (d) Latham, M. D.; King, C.
K.; Gorycki, P.; Macdonald, T. L.; Ross, W. E. Cancer Chemother.
Pharmacol. 1989, 24, 167-171. (e) Dalal, N. S.; Shi, X. Biochemistry 1989,
28, 748-750.
(7) Wendt, J. A.; Gauvreau, P. J.; Bach, R. D. J. Am. Chem. Soc. 1994,
116, 9921-9926.
(8) (a) Boger, D. L.; Hu¨ter, O.; Mbiya, K.; Zhang, M. J. Am. Chem.
Soc. 1995, 117, 11839-11849. (b) Boger, D. L. J. Heterocycl. Chem. 1996,
33, 1519-1531.
10.1021/ja0035699 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/17/2001

EnantioselectiVe Total Synthesis of Fredericamycin A
J. Am. Chem. Soc., Vol. 123, No. 14, 2001 3215
Scheme 1. Reported Total Synthesis of Fredericamycin A
(1)
difficult.13 For the purpose of the synthesis of the optically active
CDEF-ring unit, we first studied the construction of the chiral
spiro center whose stereochemistry could be easily determined.
As a new approach to the chiral spiro compounds,14,15 we
planned to use the stereoselective rearrangement of the optically
active cyclic 2,3-epoxy acylates for the following five reasons:
16,17
(i) acyloxy epoxides are easily constructed in optically
active forms from the optically active allyl alcohols, (ii) many
methodologies are available for the synthesis of optically active
allyl alcohols, (iii) it is easy to determine the absolute config-
uration of the allyl alcohol systems, (iv) the absolute configura-
tions of the spiro centers produced are readily determined if
the rearrangement proceeds in a stereoselective manner, and (v)
the acyloxy group would suppress the rearrangement of sub-
stituent on the carbon attached to the acyloxy group because of
its electron-withdrawing nature, although most epoxy alcohol
derivatives such as siloxy, alkoxy, and hydroxy groups tend to
(12) We are also investigating a different approach to the total synthesis
of 1 based on the intramolecular [4+2]-cycloaddition approach; see: (a)
Kita, Y.; Okunaka, R.; Honda, T.; Shindo, M.; Tamura, O. Tetrahedron
Lett. 1989, 30, 3995-3998. (b) Kita, Y.; Okunaka, R.; Honda, T.; Kondo,
M.; Tamura, O.; Tamura, Y. Chem. Pharm. Bull. 1991, 39, 2106-2114.
(c) Akai, S.; Iio, K.; Takeda, Y.; Ueno, H.; Kita, Y. Synlett 1997, 310-
312. (d) Kita, Y.; Akai, S.; Fujioka, H. Yuki Gosei Kagaku Kyokaishi 1998,
56, 963-974 [Chem. Abstr. 1998, 129, 343342]. (e) Kita, Y.; Iio, K.;
Kawaguchi, K.; Fukuda, N.; Takeda, Y.; Ueno,. H.; Okunaka, R.; Higuchi,
K.; Tujino, T.; Fujioka, H.; Akai, S. Chem. Eur. J. 2000, 6, 3897-3905. A
related intramolecular approach was reported separately; see: Toyota, M.;
Terashima, S. Tetrahedron Lett. 1989, 30, 829-832.
Scheme 2. Our Synthetic Plan for Optically Active
Fredericamycin A (1)
(13) For reviews of the asymmetric synthesis of the quaternary carbon
center containing a spiro carbon center, see: (a) Fuji, K. Chem. ReV. 1993,
93, 2037-2066. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.
Ed. 1998 37, 388-401.
(14) For recent examples of spirocyclane systems, see: (a) Bach, R. D.;
Tubergen, M. W.; Klix, R. C. Tetrahedron Lett. 1986, 27, 3565-3568. (b)
Rao, A. V. R.; Singh, A. K.; Reddy, K. M.; Ravikumar, K. J. Chem. Soc.,
Perkin Trans. 1 1993, 3171-3175. (c) Kuroda, C.; Hirono, Y. Tetrahedron
Lett. 1994, 35, 6895-6896. (d) Provencal, D. P.; Leahy, J. W. J. Org. Chem.
1994, 59, 5496-5498. (e) Mandai, T.; Tsujiguchi, Y.; Tsuji, J.; Saito, S.
Tetrahedron Lett. 1994, 35, 5701-5704. (f) Fuchs, K.; Paquette, L. A. J.
Org. Chem. 1994, 59, 528-532. (g) Sands, R. D. J. Org. Chem. 1994, 59,
468-471. (h) Kessar, S. V.; Vohra, R.; Kaur, N. P.; Singh, K. N.; Singh,
P. J. Chem. Soc., Chem. Commun. 1994, 1327-1328. (i) Hatsui, T.; Wang,
J.-J.; Ikeda, S.; Takeshita, H. Synlett 1995, 35-37. (j) Patra, D.; Ghosh, S.
J. Chem. Soc., Perkin Trans. 1 1995, 2635-2641. (k) Kno¨lker, H.-J.; Jones,
P. G.; Graf, R. Synlett 1996, 1155-1158. (l) Sattelkau, T.; Hollmann, C.;
Eilbracht, P. Synlett 1996, 1221-1223. (m) Trost, B. M.; Chen, D. W. C.
J. Am. Chem. Soc. 1996, 118, 12541-12554. (n) Tokunaga, Y.; Yagihashi,
M.; Ihara, M.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1997, 189-
190. (o) Baskaran, S.; Nagy, E.; Braun, M. Liebigs Ann./ Recl. 1997 311-
312. (p) Crane, S. N.; Burnell, D. J. J. Org. Chem. 1998, 63, 5708-5710.
For reviews, see: Krapcho, A. P. Synthesis 1978, 77-126.
(15) For recent examples of asymmetric synthesis of the chiral spiro-
cyclane systems, see: (a) Kno¨lker, H.-J.; Graf, R. Tetrahedron Lett. 1993,
34, 4765-4768. (b) Chitkul, B.; Pinyopronpanich, Y.; Thebtaranonth, C.;
Thebtaranonth, Y.; Taylor, W. C. Tetrahedron Lett. 1994, 35, 1099-1102.
(c) Galvez, J. M. G.; Angers, P.; Canonne, P. Tetrahedron Lett. 1994, 35,
2849-2852. (d) Maezaki, N.; Fukuyama, H.; Yagi, S.; Tanaka, T.; Iwata,
C. J. Chem. Soc., Chem. Commun. 1994, 1835-1836. (e) Huang, H.;
Forsyth, C. J. J. Org. Chem. 1995, 60, 2773-2779. (f) Villar, J. M.; Delgado,
A.; Llebaria, A.; Moreto´, J. M. Tetrahedron: Asymmetry 1995, 6, 665-
668. (g) Zhu, Y.-Y.; Burnell, D. J. Tetrahedron: Asymmetry 1996, 7, 3295-
3304. (h) Takemoto, Y.; Kuraoka, S.; Ohra, T.; Yonetoku, Y.; Iwata, C.
Tetrahedron, 1997, 53, 603-616 and references therein. For review, see:
(i) Murai, A. Yuki Gosei Kagaku Kyokaishi 1981, 39, 893-908 [Chem.
Abstr. 1981, 96, 52511]. (j) Sannigrahi, M. Terahedron 1999, 55, 9007-
9071.
ring unit would afford the optically active fredericamycin A.
The success of this synthesis would supply a way to synthesize
various analogues because various types of homophthalic
anhydrides are available as the AB-ring unit. According to our
synthetic plan, we recently communicated the first asymmetric
total synthesis of 111,12 and succeeded in determining its absolute
configuration. In this paper, we describe the full details of our
study on the synthesis of optically active 1.
Synthesis of Optically Active CDEF-Ring Unit: Construc-
tion of Optically Active Spiro Centers. The determination of
the absolute stereochemistry of the spiro center is usually
(9) (a) Boger, D. L.; Jacobson, I. C. J. Org. Chem. 1991, 56, 2115-
2112. (b) Kelly, T. R.; Li, Q.; Lohray, V. B. U.S. Patent 5166208 [Chem.
Abstr. 1993, 118, 191434]. (c) Clive, D. L. J.; Kong, X.; Paul, C. C.
Tetrahedron 1996, 52, 6085-6116. See also: (d) Hasegawa, H.; Yokoi,
K.; Narita, M.; Asaoka, T.; Kukita, K.; Ishizeki, S.; Nakajima, T. Japanese
Patent 60152468 [Chem. Abstr. 1986, 104, 33948]. (e) Hasegawa, H.; Yokoi,
K.; Narita, M.; Asaoka, T.; Kukita, K.; Ishizeki, S.; Nakajima, T. Japanese
Patent 61044868 [Chem. Abstr. 1986, 105, 97256]. (f) Hasegawa, H.; Yokoi,
K.; Narita, M.; Asaoka, T.; Kukita, K.; Ishizeki, S.; Nakajima, T. Japanese
Patent 61044867 [Chem. Abstr. 1987, 106, 49879].
(10) Application of this method to the total syntheses of peri-hydroxy
polyaromatic compounds: (a) Tamura, Y.; Sasho, M.; Nakagawa, K.;
Tsugoshi, T.; Kita, Y. J. Org. Chem. 1984, 49, 473-478. (b) Tamura, Y.;
Kita, Y. Yuki Gosei Kagaku Kyokaishi 1988, 46, 205-217 [Chem. Abstr.
1988, 109, 129465d]. (c) Kita, Y.; Takeda, Y. Kagaku to Kogyo (Osaka)
1997, 71, 298-309 [Chem. Abstr. 1997, 127, 190540n]. (d) Kirihara, M.;
Kita, Y. Heterocycles 1997, 46, 705-726. See also other examples done
by other groups: (e) Matsuda, F.; Kawasaki, M.; Ohsaki, M.; Yamada, K.;
Terashima, S. Tetrahedron 1988, 44, 5745-5759. (f) Lavalle´e, J.-F.; Rej,
R.; Courchesne, M.; Nguyen, D.; Attardo, G. Tetrahedron Lett. 1993, 34,
3519-3522. (g) Matsumoto, T.; Yamaguchi, H.; Suzuki, K. Synlett 1996,
433-434. (h) Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.;
Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 9509-9525.
(16) For reviews on the Lewis acid-mediated rearrangement of epoxides,
see: (a) Parker, R. E.; Isaacs, N. S. Chem. ReV. 1959, 59, 737-799. (b)
Rickborn, B. In ComprehensiVe Organic Synthesis, Carbon-Carbon σ-Bond
Formation; Pattenden, G., Ed.; Pergamon Press: Oxford, 1991; Vol. 3,
Chapter 3.3, pp 733-775.
(17) For examples of rearrangement of the epoxy acetates, see: (a)
Coxon, J. M.; Hartshorn, M. P.; Kirk, D. N. Tetrahedron 1964, 20, 2531-
2545. (b) Coxon, J. M.; Hartshorn, M. P.; Kirk, D. N. Tetrahedron 1964,
20, 2547-2552. In these cases, however, the yields of the rearranged
products were very low and the regioselective cleavage of the oxirane ring
was not observed.
(11) Preliminary communication: Kita, Y.; Higuchi, K.; Yoshida, Y.;
Iio, K.; Kitagaki, S.; Akai, S.; Fujioka, H. Angew. Chem., Int. Ed. 1999,
38, 683-686.

3216 J. Am. Chem. Soc., Vol. 123, No. 14, 2001
Kita et al.
Scheme 3. Synthetic Plan for the Optically Active Spiro
Scheme 4. Synthesis of Racemic Epoxy Acylates
Compounds
cause the rearrangement of a substituent next to the alcohol
function.18
Our synthetic plan for the optically active spiro compounds
is outlined in Scheme 3. Optically active epoxy acylates could
be synthesized from enones by asymmetric reduction followed
by stereoselective epoxidation and acylation. Although an
acyloxy group is known as a neighboring participating group,
if such participation could be suppressed, the desired rearrange-
ment would proceed.19 Although the electron-withdrawing
nature of the acyloxy alkyl group makes the formation of the
C2-carbocation unfavorable, the phenyl ring would effect more
strongly the formation of the C2-carbocation intermediate,20
which causes ring contraction leading to the spiro compounds.
The optically active spiro compounds would then be constructed
by stereoselective rearrangement from the optically active
tricyclic epoxy acylates whose absolute configuration could be
determined easily.21
Scheme 5. Reaction of Tricyclic Epoxy Acylates 5a-c
To examine the above concept, we initially investigated the
reactions of racemic tricyclic cis- and trans-2,3-epoxy acylates
(cis-(()-5 and trans-(()-5). They were stereoselectively syn-
thesized from the enone 2.22 Thus, reduction of 2 with DIBAL-H
afforded the allyl alcohol (()-3, which was epoxidized by the
stereoselective Sharpless condition23 to give the cis-2,3-epoxy
alcohol (()-4 as a single isomer. Acylation of (()-4 gave the
cis-2,3-epoxy acylates, cis-(()-5a,b. Mitsunobu reaction24 of
(()-4 in the presence of benzoic acid or p-nitrobenzoic acid
afforded the trans-2,3-epoxy acylates, trans-(()-5a-c (Scheme
4).
Treatment of cis-(()-5 with 1 equiv of BF3‚Et2O in CH2Cl2
at 0 °C25 afforded undesired products: the enone 2 (93%) from
(18) (a) Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.;
Shimazaki, M.; Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 3827-3829.
(b) Suzuki, K.; Miyazawa, M.; Tsuchihashi, G. Tetrahedron Lett. 1987,
28, 3515-3518. (c) Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G.
Tetrahedron Lett. 1987, 28, 5891-5894. (d) Maruoka, K.; Ooi, T.;
Nagahara, S.; Yamamoto, H. Tetrahedron 1991, 47, 6983-6998. (e)
Maruoka, K.; Sato, J.; Yamamoto, H. Tetrahedron 1992, 48, 3749-3762
and references therein. (f) Marson, C. M.; Walker, A. J.; J. Pickering, J.;
Hobson, A. D. J. Org. Chem. 1993, 58, 5944-5951.
(19) This type of rearrangement was achieved by us. (a) Fujioka, H.;
Kitagaki, S.; Imai, R.; Kondo, M.; Okamoto, S.; Yoshida, Y.; Akai, S.;
Kita, Y. Tetrahedron Lett. 1995, 36, 3219-3222. (b) Kita, Y.; Kitagaki,
S.; Yoshida, Y.; Mihara, S.; Fang, D.-F.; Fujioka, H. Tetrahedron Lett.
1997, 38, 1061-1064. (c) Kita, Y.; Kitagaki, S.; Yoshida, Y.; Mihara, S.;
Fang, D.-F.; Kondo, M.; Okamoto, S.; Imai, R.; Akai, S.; Fujioka, H. J.
Org. Chem. 1997, 62, 4991-4997. (d) Kita, Y.; Yoshida, Y.; Kitagaki, S.;
Mihara, S.; Fang, D.-F.; Furukawa, A.; Higuchi, K.; Fujioka, H. Tetrahedron
1999, 55, 4979-4998.
cis-(()-5a and the orthoester 6 (41%) from cis-(()-5b.26 On
the other hand, treatment of trans-(()-5a-c with BF3‚Et2O
under similar conditions gave the desired spiro products (()-
7a-c in good yields, respectively (Scheme 5). The same
tendency was observed in the reactions with other Lewis acids,
such as SnCl4 and CF3SO3SiMe3. No spiro compound was
obtained from cis-(()-5a, whereas the trans-(()-5a afforded
(()-7a in 89% yield with SnCl4 and 29% yield with CF3SO3-
SiMe3. The stereochemistry of (()-7a, which was confirmed
by X-ray analysis, showed that the benzene ring is laid anti to
the acyloxy group as was expected by the stereoselective
reaction sequence.27 The explanation for these reactions is as
follows. In tricyclic cis-epoxy acylates, a benzylic cation is
formed first, and the hydride at the anti periplanar position shifts
(20) It is well-known that phenyl ring stabilizes its benzylic cation
strongly. It was also proved in the rearrangement of cyclic 2,3-epoxy acylates
by us. Kita, Y.; Furukawa, A.; Futamura, J.; Higuchi, K.; Ueda, K.; Fujioka,
H. Tetrahedron Lett. 2000, 41, 2133-2136.
(21) Preliminary communication: Kita, Y.; Kitagaki, S.; Imai, R.;
Okamoto, S.; Mihara, S.; Yoshida, Y.; Akai, S.; Fujioka, H. Tetrahedron
Lett. 1996, 37, 1817-1820.
(22) Compound 2 was prepared from 2,3-dihydrobenz[g]inden-1-one
(Grissom, J. W.; Klingberg, D.; Meyenburg, S.; Stallman, B. L. J. Org.
Chem. 1994, 59, 7876-7888), which was prepared from 2-naphthaldehyde
based on the synthetic procedure for a similar compound: (a) McCloskey,
P. J. Chem. Soc. 1965, 3811-3825. (b) Mejer, S. Bull. Acta Polon. Sci.
Ser. Sci. Chim. 1962, 10, 469-473.
(23) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136-6137.
(24) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380-
2382. Review: Mitsunobu, O. Synthesis 1981, 1-28 and references therein.
(25) For synthetic studies of the spiro skeleton by acid-catalyzed
rearrangement of epoxy derivatives, see: Bach, R. D.; Tubergen, M. W.;
Klix, R. C. Tetrahedron Lett. 1986, 27, 3565-3568 and references therein.
(26) Almost quantitative formation of 6 was observed by TLC analysis.
Compound 6 was rather unstable and a fair amount of the enone 2 was
formed during purification of 6 (SiO2 column separation). In the case of
cis-5a, the formation of the orthoester was not detected even by TLC
examination.
(27) Crystallographic data for the structures reported in this paper have
been deposited with the Cambridge Crystallogrpahic Data Center as
supplementary publication no. CCDC-152839 [for (()-7a], 152840 [(-)-
10], 152841 [for (+)-11], 102892 [for (-)-25], 102893 [for (+)-26], and
102894 (for 34).

EnantioselectiVe Total Synthesis of Fredericamycin A
J. Am. Chem. Soc., Vol. 123, No. 14, 2001 3217
in the case of cis-(()-5a (R ) Ph) because of the steric
hindrance to the cation center and the hydride occupies the
position suitable for rearrangement (route a). However in the
case of cis-(()-5b (R ) Me), steric hindrance between the cation
center and the methyl group does not give the same rearrange-
ment and the formation of the orthoester 6 proceeds predomi-
nantly (route b). On the other hand, the hydride next to the
acyloxy group does not occupy the position suitable for
rearrangement in the cases of trans-epoxy acylates (trans-(()-
5a-c), and the formation of the five-membered ring by the
neighboring participation of the acyloxy group is unfavorable
because the resulting tetracyclic compound is not stable due to
the cis, trans-five-, five-, six-membered-ring junctions.
Scheme 8. Rearrangement of Optically Active Epoxy
Acylates (-)-5a and (-)-10
The acyloxy group is essential for the present rearrangement
reaction. Thus, the cis- and trans-epoxy alcohols (()-4a, and
the ethers (()-4b,c with 1 equiv of BF3‚Et2O afforded the enone
2 (Scheme 6). The different reactivity of the epoxy alcohol
Scheme 6. Rearrangement of Epoxy Alcohol 4a and Ethers
4b,c
derivatives is rationalized by the electronic nature of the alcohol
moiety. The cleavage of the oxirane ring occurs at the benzylic
position in all cases, and the electron-donating group X in (()-
4a-c (X ) H, t-BuMe2Si, Me) accelerates the hydride shift
rather than the skeletal rearrangement. In contrast, the electron-
withdrawing acyloxy groups would decrease the tendency of
the hydride shift. In these cases, the relative stereochemistry of
the hydride and the newly formed carbocation is very important.
Only in the case where the hydride lays syn to the cleaving
oxirane ring, the hydride shift is prevented and a skeletal
rearrangement occurs.
Scheme 9. Direct Hydrolysis of â-Acyloxy Ketone (+)-11
This rearrangement was successfully applied to the methoxy-
substituted trans-epoxy acylate (trans-(()-8), and its generality
was proven (Scheme 7). With the successful conversion of the
stereoselectivity, the optically pure (-)-10 could be obtained
after one recrystallization of crude (-)-10 from CH2Cl2-hexane.
The treatment of optically pure (-)-10 with BF3‚Et2O gave the
optically pure (100% de) spiro compound (+)-11 in 89% yield.
The absolute stereochemistries of trans-(-)-5a and (+)-7a were
deduced from the reaction mechanisms and finally confirmed
by the X-ray analysis of the camphanoate (-)-10 and the spiro
compound (+)-11.27 The discrimination of the two carbonyl
groups of (+)-11 was next studied. Conversion of (+)-11 to
the optically pure chiral spiro-1,3-dione derivative (+)-12 was
achieved in a three-step sequence in 77% overall yield. First
we protected the ketone as an acetal. Without protection of the
keto group of (+)-11 as an acetal, retro-aldol and aldol reaction
occurred during hydrolysis, which resulted in the racemization
of the spiro center (Scheme 9). Acetalization of (+)-11 by
Noyori’s method followed by hydrolysis of the acylate yielded
the acetal alcohol, which was subjected to PCC oxidation to
give the keto acetal (+)-12.
Scheme 7. Rearrangement of Methoxy-Substituted Epoxy
Acylates 8
trans-epoxy acylates to the chiral spiro compounds in hand, we
next examined in the optically active system (Scheme 8).
Asymmetric reduction of 2 by Corey’s method28 afforded (-)-3
whose optical purity (90% ee) was determined by the 1H NMR
analysis of its benzoate (-)-3a using the chiral shift reagent,
Eu(hfc)3. Epoxidation of (-)-3 by the stereoselective Sharpless
epoxidation afforded cis-(-)-4 as a sole product. The Mitsunobu
reaction of cis-(-)-4 gave trans-(-)-5a (90% ee) in 89% yield.
Treatment of trans-(-)-5a with BF3‚Et2O afforded (+)-7a in
89% yield with retention of optical purity (90% ee). This means
that the rearrangement occurs stereospecifically. Although the
asymmetric reduction of 2 did not proceed with sufficient
As mentioned above, we have developed a new stereoselec-
tive synthesis of the chiral, nonracemic spiro[cyclopentane-1,1′-
indan]-2,5-dione system found in 1. We then applied this
methodology to the synthesis of the CDEF-ring unit of 1.
The tetracyclic hydroxy ketone 18 was prepared from the
tricyclic keto aldehyde 17 synthesized in two ways. First, we
prepared 17 by a modification of Clive’s procedure.29 Thus,
(28) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V.
K. J. Am. Chem. Soc. 1987, 109, 7925-7926. Review: Corey, E. J.; Helal,
C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-2012. (b) The signal HA of
(-)-3a is most affected by the shift reagent. (Baseline separation at 11.5
and 11.9 ppm.)
(29) Clive, D. L. J.; Sedgeworth, J. J. Heterocycl. Chem. 1987, 24, 509-
511.

3218 J. Am. Chem. Soc., Vol. 123, No. 14, 2001
Kita et al.
Scheme 10. Synthesis of Tetracyclic R-Hydroxy Ketone 18
This is due to the steric hindrance of the tertiary hydroxy group
(entries 6-8). However, the reaction of 18 with the Burgess
reagent34 in refluxing THF proceeded smoothly to give the enone
22 quantitatively (entry 10), whereas the reaction in refluxing
benzene did not work at all and the starting material was
recovered (Scheme 11).
Scheme 12. Synthesis of Tetracyclic Vinyl Sulfoxide 30
Table 1. Dehydroxylation of Tetracyclic R-Hydroxy Ketone 18
entry
reaction conditions
PPTS, CH2Cl2, reflux
p-TsOH, CH2Cl2, reflux
yield of 22
1
2
trace
trace
3
4
5
(1) MsCl, Et3N, CH2Cl2; (2) DBU
SOCl2, pyridine, -10 °C
HCO2H, H2SO4, 60 °C
trace
43%
51%
6
7
8
9
NaOH, CS2, MeI, toluene, r.t. ∼ reflux
no reaction
NaOH, CS2, MeI, Et2O-CHCl3, r.t. ∼ reflux no reaction
NaOH, CS2, MeI, Et2O, r.t. ∼ reflux
Burgess reagent, C6H6, 50 °C ∼ reflux
Burgess reagent, THF, reflux
no reaction
no reaction
quantitative
10
Scheme 11. cis-Elimination by Burgess Reagent
the reaction between methyl 2-methoxy-4,6-dimethylpyridine-
3-carboxylate 14 treated with LDA and R′-substituted cyclo-
hexenone 15 proceeded to the 1,4-addition and Claisen-type
condensation to give the coupling product, whose E-ring was
aromatized by DDQ. Methylation of the phenolic hydroxy
function, desilylation, and then Swern oxidation30 gave 17 in
29% overall yield. Intramolecular pinacol coupling of 17 with
SmI2 gave the diol,31 which was oxidized by Swern’s method
to give the hydroxy ketone 18 in 62% yield from 17. The same
aldehyde 17 was alternatively prepared by the strong base-
induced cycloaddition of homophthalic anhydride 19 with
R-sulfinylenone 20 in 37% overall yield32 (Scheme 10).
The formation of enone from 18 by dehydration was first
studied under acidic conditions (Table 1, entries 1-5). Treat-
ment of 18 with H2SO4/HCO2H gave the enone 22 in 51% yield
(entry 5). This result was reported in the preliminary com-
munication.11 The yield of dehydration was not satisfactory,
therefore we next examined the cis-elimination reaction. The
Chugaev reaction,33 a typical cis-elimination reaction, was first
examined for 18, but it failed to form the requisite thioester.
Corey’s asymmetric reduction of 22 using the chiral borane
reagent and BH3‚Me2S gave a quantitative yield of the (R)-
alcohol (+)-23 with 74% ee. The asymmetric reduction with
the chiral borane, prepared in situ, and BH3‚Me2S was also
examined.35 However, no improvement in ee could be achieved
(47% ee). Sharpless epoxidation of (+)-23 (74% ee) afforded
stereoselectively the cis-epoxy alcohol (-)-24 (81%, 74% ee),
which was treated with (-)-camphanic acid (>98% ee) under
Mitsunobu conditions to give the mixture of diastereomers (74%
de) of the trans-epoxy camphanate (-)-25. This mixture of
diastereomers was separated by SiO2-column chromatography
to give the optically pure (-)-25 (g99% de). The absolute
stereochemistry of (-)-25 was determined by X-ray crystal-
lographic analysis.27 The rearrangement reaction of (-)-25
(g99% de) with BF3‚Et2O proceeded at 0 °C to give the
optically pure spiro compound (+)-26 (g99% de in 94% yield).
The rearrangement reaction of (-)-25 (74% de) with BF3‚Et2O
gave a 94% yield of the spiro compound (+)-26 (g74% de),
which was used as the standard sample for HPLC analysis, and
the rearrangement reaction of this compound was found to
proceed with perfect stereoselectivity. Based on our model study
described above, the stereochemistry of (+)-26 was envisaged
as depicted in Scheme 12 and finally ascertained by its X-ray
crystallographic analysis.27 The transformation of (+)-26 to the
vinyl sulfoxide 30 was achieved retaining the chiral integrity
by taking into consideration the following two points. The first
(30) Omura, K.; Sharma, A. K.; Swern, D. J. Org. Chem. 1976, 41, 957-
962.
(31) (a) Chiara, J. L.; Cabri, W.; Hanessian, S. Tetrahedron Lett. 1991,
32, 1125-1128. (b) Uenishi, J.; Masuda, S.; Wakabayashi, S. Tetrahedron
Lett. 1991, 32, 5097-5100.
(32) (a) Kita, Y.; Iio, K.; Okajima, A.; Takeda, Y.; Kawaguchi, K.;
Whelan, B. A.; Akai, S. Synlett 1998, 292-294. (b) Iio, K.; Ramesh, N.
G.; Okajima, A.; Higuchi, K.; Fujioka, H.; Akai, S.; Kita, Y. J. Org. Chem.
2000, 65, 89-95.
(33) (a) Depuy, C. H.; King, R. W. Chem. ReV. 1960, 60, 431-457. (b)
Nace, H. R. Org. React. 1962, 12, 57-100.
(34) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem.
1973, 38, 26-31.
(35) Masui, M.; Shioiri, T. Synlett 1997, 273-274.

EnantioselectiVe Total Synthesis of Fredericamycin A
J. Am. Chem. Soc., Vol. 123, No. 14, 2001 3219
point is the acetalization of (+)-26 prior to the alkaline
hydrolysis to prevent the easy racemization of the spiro center
by retro-aldol and aldol reaction. In fact, without acetalization
of (+)-26, easy racemization of the spiro center occurred in
this compound. The second point is the introduction of a sulfinyl
group. Based on our recent study,32 a sulfinyl group was
estimated as a powerful directing and activating substituent on
the dienophile. Treatment of the keto acetal (+)-28 with lithium
bis(trimethylsilyl)amide and PhSSO2Ph afforded the R,R-
diphenylsulfenyl compound (+)-29. Acid treatment of (+)-29
caused deacetalization and elimination of PhSH to give the
diketovinyl sulfide, which was then oxidized with mCPBA, and
the optically active CDEF-ring unit 30 was obtained as a
diastereo mixture at sulfur centers (approximately 1:1) (Scheme
12).
Scheme 14. Synthesis of Homophthalic Anhydrides 35 and
36
Synthesis of the AB-Ring Unit. Because the absolute
stereochemistry of 1 was unknown, two regioisomers of the AB-
ring units, suitably functionalized homophthalic anhydride
derivatives, were necessary, which allows the synthesis of both
enantiomers (S)- and (R)-1, respectively.
Homophthalic anhydride derivatives are generally obtained
from the corresponding homophthalic acid derivatives, which
are prepared by several methodologies such as (1) ortho-
lithiation of benzoic acid derivatives,36a (2) cycloaddition
reaction of allenyl esters to dienes,36b and (3) addition of
malonate anion to benzynes36c (Scheme 13).
the corresponding anhydrides 35 and 36, respectively. In the
case of 34, a careful workup with trifluoroacetic acid instead
of aqueous HCl was necessary since the dicarboxylic acid
formed after alkaline hydrolysis was found to be somewhat
unstable in the acidic condition. The regiochemistry of the
products was deduced by the nuclear Overhauser effect (NOE)
experiment with the benzyl ether derivatives of 3339 and finally
confirmed by X-ray crystallographic analysis of 34.27
Intermolecular [4+2]-Cyclocondensation10 and Total Syn-
thesis of Optically Active Fredericamycin A (1) and ent-1.
The three-step sequences, (1) treatment of 35 with 1.15 equiv
of NaH, (2) [4+2]-cyclocondensation with 30, and (3) methy-
lation of hydroxyl group, afforded the hexacyclic product (S)-
38 (76%, 97% ee). Its enantiomer (R)-38 (71%, 94% ee) was
obtained by using 36 in place of 35 in the above reaction
(Scheme 15). CD spectra of these products showed symmetrical
curves (Figure 1) and among them the CD spectra of the (S)-
isomer closely resembled that of the fully protected 1 reported
by Boger’s group.8a We then first studied the conversion of (S)-
38. Selective demethylation of the methyl ether on the F-ring
of (S)-38 by NaBr and p-TsOH3b gave the R-pyridone com-
pound, which was oxidized with SeO2 to give (S)-39.40 The
Wittig reaction3 of (S)-39 with trans-2-butenyl triphenylphos-
phonium bromide gave a 5 to 1 mixture of (E,E)- and (E,Z)-
side chain isomers in 46% yield. An attempt for assembling
the mixture of side chain isomers to one isomer, (E,E)-form,
Scheme 13. Preparation of Homophthalic Anhydrides
Among them, we chose the method with the benzyne
intermediate (ref 36c) because this method is quite simple and
would afford two regioisomers in one operation. The regioiso-
meric diene parts 35 and 36 were prepared from 31 with some
modifications of the reported method (Scheme 14).36c Reaction
of 3137 with dimethyl malonate (2.0 equiv), n-BuLi (3.0 equiv),
and tetramethylpiperidine (1.5 equiv) afforded a regioisomeric
mixture (2:3) of the homophthalates 32 and 33 through a
nonregioselective addition of the lithiomalonate to the benzyne
intermediate. Each regioisomer was readily separated by SiO2
column chromatography to give the pure 32 and 33, which were
subjected to sequential bromination and methanolysis to give
the respective dimethyl esters. Alkaline hydrolysis of these
dimethyl esters followed by dehydration of the resulting
dicarboxylic acid with trimethylsilyl(ethoxy)acetylene38 afforded
3b
by isomerization of olefins with Br2, TMSI,4b or I2 did not
work at all and the starting mixture was recovered. Deprotection
of the mixture with BBr3 (12.5 equiv) and subsequent autoxi-
dation afforded a 5 to 1 mixture of 1 and its (E,Z)-side chain
isomer in a total yield of 74%. The pure 1 was obtained in 40%
yield after purification by HPLC column (Jasco Megapak SIL
NH2-10, 1 × 25 cm, 800:200:1 CHCl3-n-hexane-acetic acid,
5.0 mL/min flow rate). Transformation of (R)-38 to ent-1 was
done in the same manner. CD spectra of natural and unnatural
enantiomers of synthetic 1 showed symmetrical curves (Figure
2).
(36) (a) For example see: Cushman, M.; Dekow, F. W. Tetrahedron
1978, 34, 1435-1439. De Silva, S. O.; Ahmad, I.; Snieckus, V. Can. J.
Chem. 1979, 57, 1598-1605. Tamura, Y.; Sasho, M.; Akai, S.; Wada, A.;
Kita, Y. Tetrahedron 1984, 40, 4539-4548. (b) For example, see: Tamura,
Y.; Fukata, F.; Tsugoshi, T.; Sasho, M.; Nakajima, Y.; Kita, Y. Chem.
Pharm. Bull. 1984, 32, 3259-3262. Roush, W. R.; Murphy, M. J. Org.
Chem. 1992, 57, 6622-6629. Langer, P.; Kracke, B. Tetrahedron Lett. 2000,
41, 4545-4547 and references therein. (c) Shair, M. D.; Yoon, T. Y.;
Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem. Soc. 1996,
118, 9509-9525.
(37) Blatchly, J. M.; McOmie, J. F. W.; Searle, J. B. J. Chem. Soc. (C)
1969, 1350-1353.
(38) Kita, Y.; Akai, S.; Ajimura, N.; Yoshigi, M.; Tsugoshi, T.; Yasuda,
H.; Tamura, Y. J. Org. Chem. 1986, 51, 4150-4158.
(39) Benzyl ether derivative of 33 was obtained by BCl3 hydrolysis of
33 followed by benzylation. NOE was observed between the methylene of
benzyl ether and the aromatic proton.
(40) Kita, Y.; Ueno, H.; Kitagaki, S.; Kobayashi, K.; Iio, K.; Akai, S. J.
Chem. Soc., Chem. Commun. 1994, 701-702.

3220 J. Am. Chem. Soc., Vol. 123, No. 14, 2001
Kita et al.
Scheme 15. Enantioselective Total Synthesis of Fredericamycin A (1) and ent-1
Figure 2. CD spectra of 1 in DMF-MeOH-Et3N.
Figure 1. CD spectra of 38 in i-PrOH.
The synthetic compound was identical in all respects {1H
NMR, IR, UV, MS, TLC, HPLC, and CD} with the authentic
material provided by the SS Pharmaceutical Co., Ltd., Japan.
CD Spectra and HPLC Charts of Intermolecular Coupled
Products and Optically Active Fredericamycin A: Deter-
mination of the Absolute Configuration. CD Spectra of
intermolecular coupled products, optically active natural and
unnatural enantiomers of synthetic 1, are shown in Figures 1
and 2. Figure 1 shows the CD spectra of the permethylates (R)-
and (S)-38, obtained by methylation of the coupled products,

EnantioselectiVe Total Synthesis of Fredericamycin A
J. Am. Chem. Soc., Vol. 123, No. 14, 2001 3221
iPrOH 92/8)) as a colorless crystal: mp 163 °C (hexane/AcOEt); [R]20
D
+9.7 (c 1.20, CHCl3); IR (KBr) 1794, 1740, 1736 cm-1; 1H NMR (270
MHz, CDCl3) δ 0.94 (6H, s), 1.09 (3H, s), 1.58-1.68 (2H, m), 1.81-
2.04 (3H, m), 2.17-2.79 (5H, m), 2.47 (3H, s), 3.02-3.25 (2H, m),
3.73 (3H, s), 4.11 (3H, s), 5.70 (1H, dd, J ) 5.5, 8.0 Hz), 6.94 (1H, s),
7.21 (1H, s); 13C NMR (68 MHz, CDCl3) δ 9.7, 16.5, 16.8, 23.7, 27.2,
28.8, 30.4, 32.2, 32.5, 36.7, 53.6, 54.3, 54.8, 62.3, 63.4, 81.4, 90.8,
111.1, 112.9, 116.9, 135.6, 143.1, 148.8, 149.2, 152.5, 158.8, 166.7,
178.2, 217.4; HRMS calcd for C29H33NO7 (M+) 507.2257, found
507.2260. Anal. Calcd for C29H33NO7: C, 68.62; H, 6.55; N, 2.76.
Found: C, 68.59; H, 6.55; N, 2.77.
(2S)-3′-Methyl-1′,4,5,6,8,9,9′-heptamethoxy-6′,7′-dihydrospiro-
[2H-benz[f]indene-2,8′-8′H-cyclopent[g]isoquinoline]-1,3-dione ((S)-
38). (a) [4+2]-Cyclocondensation: NaH (16 mg, 60% in mineral oil,
0.39 mmol) was added to a solution of 35 (94 mg, 0.33 mmol) in THF
(4.0 mL) at 0 °C under Ar atmosphere, and the resulting mixture was
stirred for 1 h at room temperature. A solution of 30 (79 mg, 0.18
mmol, 97% ee) in THF (5.0 mL) was added dropwise to the mixture
cooled to 0 °C, and the reaction mixture was stirred for 7 h at room
temperature. Saturated aqueous NH4Cl was added to the reaction
mixture cooled in an ice-water bath, and the resulting solution was
extracted with AcOEt and CH2Cl2. Each organic layer was washed with
brine, dried over Na2SO4, and concentrated in vacuo, respectively. The
combined residue was purified by SiO2 column chromatography with
CH2Cl2-MeOH (50/1) as an eluent to give (S)-37 (86 mg, 87%, 97%
ee by HPLC (CHIRALPAK AD, flow rate 0.9 mL/min, Hex/iPrOH
Figure 3. HPLC chart of (S)-38.
70/30)) as a yellow solid: mp 102 °C; [R]19 +50.2 (c 1.07, CHCl3);
D
1
IR (KBr) >3000, 1727, 1703 cm-1; H NMR (300 MHz, CDCl3) δ
2.39 (3H, s), 2.47 (2H, t, J ) 7.5 Hz), 3.32 (2H, t, J ) 7.5 Hz), 3.45
(3H, s), 3.93 (9H, s), 3.95 (3H, s), 3.98 (3H, s), 6.82 (1H, s), 6.88 (1H,
s), 7.24 (1H, s), 11.00 (1H, brs); 13C NMR (75 MHz, CDCl3) δ 23.7,
32.4, 35.9, 53.5, 56.7, 57.4, 62.5, 62.6, 62.9, 66.1, 100.4, 111.0, 113.0,
117.2, 118.2, 120.7, 123.6, 125.1, 134.2, 139.8, 143.2, 148.7, 149.5,
150.0, 151.2, 151.9, 152.5, 156.9, 158.9, 199.5, 202.8; HRMS calcd
for C31H29NO9 (M+) 559.1842, found 559.1833.
Figure 4. HPLC chart of (R)-38.
(b) Methylation: K2CO3 (0.14 g, 1.0 mmol) and MeI (0.12 mL, 2.0
mmol) were added to a solution of the above product (56 mg, 0.10
mmol) in DMF (6.0 mL) at 0 °C under N2 atmosphere, and the resulting
mixture was stirred for 1 h at room temperature. Saturated aqueous
NH4Cl was added to the reaction mixture cooled in an ice-water bath,
and the resulting solution was extracted with Et2O. The organic layer
was washed with brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by SiO2 column chromatography with
hexane-AcOEt (1/2) as an eluent to give (S)-38 (49 mg, 87%, 97% ee
by HPLC (CHIRALPAK AD, flow rate 1.0 mL/min, Hex/iPrOH 70/
showing symmetrical curves, among which that of (S)-38
showed a similar CD pattern as that of Boger’s fully protected
natural enantiomer of 1.8a Figure 2 shows the CD spectra of
optically active synthetic 1 (97% ee) and its enantiomer (94%
ee). The curve of the synthetic 1 from the AB-ring part 35 is
identical with that of natural 1. Thus, the absolute configuration
of natural 1 was ascertained to be S. Figures 3 and 4 show HPLC
analyses of the permethylates (R)- and (S)-38, from which their
ee values could be deduced.
30)) as a yellow solid: mp 98 °C; [R]19 +15.9 (c 0.76, CHCl3); CD
D
i
(c 1.1 × 10-5, PrOH) [θ]20 (nm) +5.9 × 104 (295), -0.98 × 104
Conclusion
max
(380); IR (KBr) 1732, 1703 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.38
(3H, s), 2.47 (2H, t, J ) 7.5 Hz), 3.33 (2H, t, J ) 7.5 Hz), 3.41 (3H,
s), 3.82 (3H, s), 3.92 (3H, s), 3.96 (3H, s), 3.99 (9H, s), 6.84 (1H, s),
6.87 (1H, s), 7.24 (1H, s); 13C NMR (75 MHz, CDCl3) δ 23.7, 32.3,
36.2, 53.4, 56.5, 57.3, 62.2, 62.5, 63.0, 63.2, 66.2, 99.7, 111.1, 112.9,
117.1, 121.1, 124.4, 127.6, 131.0, 134.5, 139.2, 143.2, 148.6, 150.0,
150.8, 152.4, 153.6, 153.9, 156.8, 158.9, 199.2, 200.4; HRMS calcd
for C32H31NO9 (M+) 573.1998, found 573.1982.
We have developed a new method for the construction of
chiral spiro centers, the chiral spiro[cyclopentane-1,1′-indan]-
2,5-dione system, through a stereospecific rearrangement of the
trans-2,3-epoxy acylates using Lewis acid. This method was
successfully applied to construct the chiral spiro center of 1
and utilized in the asymmetric total synthesis of 1 and ent-1 in
combination with strong-base-induced [4+2]-cyclocondensation.
This is the first asymmetric total synthesis of 1 and ent-1, which
establishes the absolute configuration of the single chiral center
of 1.
(2S)-3′-Formyl-4,5,6,8,9,9′-hexamethoxy-6′,7′-dihydrospiro[2H-
benz[f]indene-2,8′-8′H-cyclopent[g]isoquinoline]-1,1′,(2′H),3-tri-
one ((S)-39). (a) Demethylation: NaBr (0.41 g, 4.0 mmol) and
p-TsOH‚H2O (0.16 g, 0.83 mmol) were added to a solution of (S)-38
(19 mg, 33 µmol) in MeOH (15 mL) at room temperature, and the
resulting solution was refluxed for 1.5 h at 80 °C. The reaction mixture
was poured into saturated aqueous NaHCO3. The mixture was extracted
with AcOEt. The organic layer was washed with H2O and brine, dried
over Na2SO4, and concentrated in vacuo. The residue was purified by
SiO2 column chromatography with CH2Cl2-AcOEt-MeOH (100/50/
6) as an eluent to give the demethylated compound (18 mg, 95%, 97%
ee by HPLC (CHIRALPAK AD, flow rate 1.0 mL/min, Hex/iPrOH
Experimental Section
Rearrangement Product ((+)-26). BF3‚Et2O (68 µL, 0.54 mmol)
was added dropwise to a solution of (-)-25 (0.14 g, 0.27 mmol) in
CH2Cl2 (7.0 mL) at 0 °C under Ar atmosphere. The resulting mixture
was stirred for 1.5 h at the same temperature. The reaction mixture
was cooled in an ice-water bath, diluted with CH2Cl2, mixed with
saturated aqueous NaHCO3, and extracted with CH2Cl2. The organic
layer was washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by SiO2 column chromatography with
hexane-AcOEt (3/1 to 2/1) as an eluent to give (+)-26 (0.13 g, 94%,
>99% de by HPLC (CHIRALPAK AD, flow rate 1.0 mL/min, Hex/
67/33)) as a yellow solid: mp 157 °C; [R]20 +24.7 (c 0.94, CHCl3);
D
1
IR (KBr) 1732, 1703, 1661, 1651, 1620 cm-1; H NMR (300 MHz,
CDCl3) δ 2.19 (3H, s), 2.51 (2H, t, J ) 7.5 Hz), 3.32 (2H, t, J ) 7.5
Hz), 3.57 (3H, s), 3.87 (3H, s), 4.01 (3H, s), 4.02 (3H, s), 4.03 (3H, s),

3222 J. Am. Chem. Soc., Vol. 123, No. 14, 2001
Kita et al.
4.04 (3H, s), 6.14 (1H, s), 6.89 (1H, s), 7.09 (1H, s,), 10.71 (1H, brs);
13C NMR (75 MHz, CDCl3) δ 18.8, 32.7, 35.8, 56.5, 57.4, 62.1, 62.2,
63.1, 63.3, 66.1, 99.6, 104.8, 116.0, 117.4, 121.1, 124.5, 127.7, 131.0,
134.8, 137.6, 139.2, 143.1, 150.8, 152.9, 153.6, 153.9, 156.1, 156.8,
162.5, 199.3, 200.5; HRMS calcd for C31H29NO9 (M+) 559.1842, found
559.1846.
for 24 h at room temperature. The mixture was extracted with AcOEt.
The organic layer was washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by SiO2 column
chromatography with CHCl3-MeOH-acetone-AcOH (93/3/3/1) and
HPLC (Jasco Megapak SIL NH2-10, 1 × 25 cm, flow rate 5.0 mL/
min, CHCl3-n-hexane-AcOH 800/200/1) to give reddish solid, natural
enantiomer of synthetic fredericamycin A (1.7 mg, 40%). The spectral
data (1H NMR, mp, IR, UV, CD, HRMS, HPLC, TLC) of the obtained
natural enantiomer of synthetic fredericamycin A agreed with those of
the natural one provided by the SS Pharmaceutical Co., Ltd., Japan.
(2R)-3′-Methyl-1′,4,5,6,8,9,9′-heptamethoxy-6′,7′-dihydrospiro-
[2H-benz[f]indene-2,8′-8′H-cyclopent[g]isoquinoline]-1,3-dione ((R)-
38). (a) [4+2]-Cyclocondensation: Similarly to the preparation of (S)-
38, a solution of 36 (19 mg, 66 µmol) in THF (0.60 mL) was added
dropwise to a suspension of NaH (3.2 mg, 60% in mineral oil, 79 µmol)
in THF (0.30 mL) at 0 °C under Ar atmosphere, and the resulting
mixture was stirred for 1.5 h at room temperature. A solution of 30
(20 mg, 44 µmol) in THF (0.60 mL) was added dropwise to the mixture
cooled to 0 °C, and the reaction mixture was stirred for 1.5 h at room
temperature. Similar workup and purification gave (R)-37 (20 mg, 83%,
94% ee by HPLC (CHIRALPAK AD, flow rate 0.9 mL/min, Hex/
(b) SeO2 oxidation: SeO2 (16 mg, 0.13 mmol) was added to a
solution of the above product (41 mg, 74 µmol) in 1,4-dioxane (7.0
mL) at room temperature, and the resulting solution was refluxed for
1.5 h at 110 °C. The mixture was filtered through a Celite pad. The
filtrate was concentrated in vacuo. The residue was purified by SiO2
column chromatography with CH2Cl2-MeOH (50/3) and CH2Cl2-
AcOEt-MeOH (50/25/2) as an eluent to give (S)-39 (32 mg, 76%,
97% ee by HPLC (CHIRALPAK AD, flow rate 1.0 mL/min, Hex/
iPrOH 70/30)) as a yellow solid: mp 258 °C; [R]20 +30.3 (c 1.32,
D
CHCl3); IR (KBr) 1732, 1701-1653 cm-1; 1H NMR (300 MHz, CDCl3)
δ 2.60 (2H, t, J ) 7.5 Hz), 3.42 (2H, t, J ) 7.5 Hz), 3.61 (3H, s), 3.89
(3H, s), 4.04 (6H, s), 4.05 (3H, s), 4.07 (3H, s), 6.92 (1H, s), 7.05 (1H,
s), 7.43 (1H, s), 8.76 (1H, brs), 9.52 (1H, s); 13C NMR (75 MHz, CDCl3)
δ 32.7, 35.7, 56.6, 57.3, 62.3, 62.7, 63.2, 63.4, 66.6, 99.7, 118.2, 120.6,
120.7, 121.0, 124.3, 127.5, 131.0, 134.8, 139.3, 139.5, 140.4, 151.1,
153.8, 154.1, 154.2, 156.9, 157.0, 159.2, 183.8, 198.5, 199.7; HRMS
calcd for C31H27NO10 (M+) 573.1634, found 573.1637.
iPrOH 70/30)) as a yellow solid: mp 118 °C; [R]20 +18.0 (c 1.11,
D
CHCl3); IR (KBr) >3000, 1728, 1701 cm-1 1H NMR (300 MHz,
;
Natural Enantiomer of Synthetic Fredericamycin A ((S)-1). trans-
2-Butenylphosphonium bromide (0.25 g, 0.63 mmol) was stirred for 1
h at room temperature under Ar atmosphere to become a powder. THF
(10 mL) was added to the powder, and the resulting mixture was cooled
to -78 °C. nBuLi (0.41 mL, 1.5 M in hexane, 0.63 mmol) was added
dropwise to the mixture, and the solution was stirred for 40 min at
room temperature to form the ylide.
CDCl3) δ 2.47 (3H, s), 2.53 (2H, t, J ) 7.5 Hz), 3.38 (2H, t, J ) 7.5
Hz), 3.52 (3H, s), 3.89 (3H, s), 4.01 (3H, s), 4.03 (3H, s), 4.08 (3H, s),
4.11 (3H, s), 6.88 (1H, s), 6.96 (1H, s), 7.32 (1H, s), 10.92 (1H, brs);
13C NMR (75 MHz, CDCl3) δ 23.7, 32.4, 35.9, 53.5, 56.6, 57.1, 62.3,
62.6, 63.2, 66.0, 97.9, 111.1, 113.0, 115.0, 115.8, 117.3, 126.4, 131.3,
134.0, 139.9, 143.3, 146.9, 148.8, 150.0, 152.6, 154.2, 154.3, 157.1,
158.9, 200.4, 202.5; HRMS calcd for C31H30NO9 (M+ + H) 560.1921,
found 560.1934.
The obtained ylide (0.49 mL, 63 mM in THF, 31 µmol), cooled to
-78 °C, was added dropwise to a solution of (S)-39 (15 mg, 26 µmol)
in THF (2.0 mL) at -78 °C under Ar atmosphere. The resulting mixture
was allowed to stand at room temperature and stirred for 6 h. MeOH
(1.0 mL) and saturated aqueous NH4Cl were added to the reaction
mixture successively, and the resulting solution was extracted with CH2-
Cl2. The organic layer was washed with brine, dried over Na2SO4, and
concentrated in vacuo, respectively. The combined residue was purified
by SiO2 column chromatography with CH2Cl2-MeOH (50/3) and
benzene-n-hexane-EtOH (5/10/2-9/10/2) as eluents to give the
yellow solid (7.1 mg, 46%, E-E:E-Z ) 5:1): mp 172 °C; IR (KBr)
(b) Methylation: Similarly to the preparation of (S)-38, K2CO3 (7.4
mg, 54 µmol) and MeI (10 µL, 0.16 mmol) were added to a solution
of the above product (6.0 mg, 11 µmol) in DMF (3.0 mL) at 0 °C in
N2 atmosphere, and the resultimg mixture was stirred for 2 h at room
temperature. Similar workup and the purification gave (R)-38 (5.2 mg,
85%, 94% ee by HPLC (CHIRALPAK AD, flow rate 1.0 mL/min,
Hex/iPrOH 70/30)) as a yellow solid. The spectroscopic data (mp, IR,
1H NMR, 13C NMR, HRMS) of (R)-38 showed good agreement with
those of (S)-38. [R]20 -15.1 (c 0.86, CHCl3); CD (c 1.30 × 10-5
,
D
iPrOH) [θ]20 (nm) -6.0 × 104 (295), +0.98 × 104 (383).
max
1
1734, 1707, 1638 cm-1; H NMR (300 MHz, CDCl3) δ 1.71 (2.5H,
Acknowledgment. This research was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education,
Science, and Culture, Japan, a Special Coordination Funds of
the Science and Technology Agency, Japan, and Japan Research
Foundation for Optically Active Compounds. We are also
grateful to Mr. Keita Matsumoto, Taisho Pharmaceutical Co.,
Ltd., for X-ray crystallographic analysis and Dr. Hiroshi
Hasegawa (SS Pharmaceutical Co., Ltd., Japan) for generously
providing an authentic sample of fredericamycin A.
major, d, J ) 7.0 Hz), 1.81 (0.5H, minor, dd, J ) 1.5, 7.0 Hz), 2.54
(2H, t, J ) 7.5 Hz), 3.35 (2H, t, J ) 7.5 Hz), 3.60 (3H, s), 3.90 (3H,
s), 4.04 (6H, s), 4.05 (3H, s), 4.07 (3H, s), 5.66-5.72 (0.17H, minor,
m), 5.88 (0.83H, major, dq, J ) 7.0, 15.0 Hz), 6.08 (1H, d, J ) 16.0
Hz), 6.15 (1H, dd, J ) 10.5, 15.0 Hz), 6.31 (0.83H, major, s), 6.35
(0.17H, minor, s), 6.67 (0.83H, major, dd, J ) 10.5, 16.0 Hz), 6.88-
7.00 (0.17H, minor, m), 6.91 (1H, s), 7.17 (0.83H, major, s), 7.19
(0.17H, minor, s), 8.93 (0.17H, minor, brs), 9.07 (0.83H, major, brs);
HRMS (FAB) calcd for C35H34NO9 (M+ + H) 612.2233, found
612.2240.
BBr3 (0.10 mL, 1.0 M in CH2Cl2, 0.10 mmol) was added to a solution
of the above solid (4.9 mg, 8.0 µmol) in CH2Cl2 (2.0 mL) at -78 °C
under Ar atmosphere. The resulting mixture was stirred for 1 h at the
same temperature. The reaction mixture was treated with H2O (2.0 mL)
and concentrated in vacuo at room temperature. THF (45 mL) and H2O
(15 mL) were added to the residue, and the resulting solution was stirred
Supporting Information Available: Experimental proce-
dures for the synthesis of model systems and NMR spectra of
all compounds lacking elemental analysis (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA0035699