Intramolecular 1,3-dipolar cycloaddition strategy for enantioselective synthesis of FR-900482 analogues

Article abstract of DOI:10.1021/ol016243t

(Equation presented) Enantioselective synthesis of FR-900482 analogues is described. The key reaction of the synthesis is intramolecular 1,3-dipolar cycloaddition of a highly functionalized nitrile oxide with complete stereo-and regioselectivities to construct the eight-membered benzazocine ring.

Full text of DOI:10.1021/ol016243t

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2575-2578
Intramolecular 1,3-Dipolar Cycloaddition
Strategy for Enantioselective Synthesis
of FR-900482 Analogues
Mika Kambe, Eri Arai, Masashi Suzuki, Hidetoshi Tokuyama, and
Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, CREST,
The Japan Science and Technology Corporation, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received June 7, 2001
ABSTRACT
Enantioselective synthesis of FR-900482 analogues is described. The key reaction of the synthesis is intramolecular 1,3-dipolar cycloaddition
of a highly functionalized nitrile oxide with complete stereo- and regioselectivities to construct the eight-membered benzazocine ring.
FR-900482 (1) was isolated in 1987 from a culture broth of
Streptomyces sandansis no. 6897 at Fujisawa Pharmaceutical
Co. Ltd.1 Biological studies have shown that FR-900482 and
related compound FK317 (2) possess exceptionally potent
antitumor activities (Figure 1).2 FR-900482 works as a DNA
developed to synthesize this compound,4 only three total
syntheses5-7 and a formal synthesis8 have been reported to
date. After completion of our first total synthesis of (()-
FR-900482, we have been involved in an enantioselective
(1) Iwami, M.; Kiyoto, S.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka,
H. J. Antibiot. 1987, 40, 589. (b) Kiyoto, S.; Shibata, T.; Yamashita, M.;
Komori, T.; Okuhara, M.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka,
H. J. Antibiot. 1987, 40, 594. (c) Uchida, I.; Takase, S.; Kayakiri, S.;
Hashimoto, M. J. Am. Chem. Soc. 1987, 109, 4108.
(2) Naoe, Y.; Inami, M.; Matsumoto, S.; Fujiwara, T.; Yamazaki, S.;
Kawamura, I.; Nishigaki, F.; Tsujimoto, S.; Manda, T.; Shimomura, K. Jpn.
J. Cancer Res. 1998, 89, 1306. (b) Naoe, Y.; Kawamura, I.; Inami, M.;
Matsumoto, S.; Nishigaki, F.; Tsujimoto, S.; Manda, T.; Shimomura, K.
Jpn. J. Cancer Res. 1998, 89, 1318.
(3) For a review, see: Williams, R. M.; Rajski, S. R. Chem. ReV. 1998,
98, 2723.
(4) For representative examples, see: (a) Rapoport, H.; Jones, R. J. J.
Org. Chem. 1990, 55, 1144. (b) Grubbs, R. H.; Miller, S. J.; Kim, S. H.;
Chen, Z. R. J. Am. Chem. Soc. 1995, 117, 2108. (c) Lim, H. J. Sulikowski,
G. A. Tetrahedron Lett. 1996, 37, 5243. (d) Ziegler, F. E.; Belema, M. J.
J. Org. Chem. 1997, 62, 1083. (e) Mithani, S.; Drew, D. M.; Rydberg, E.
H.; Taylor, N. J.; Mooibroek, S. Dmitrienko, G. I. J. Am. Chem. Soc. 1997,
119, 1159. (f) Rollins, S. B.; Williams, R. M. Tetrahedron Lett. 1997, 38,
4033.
(5) Fukuyama, T.; Goto, S. Tetrahedron Lett. 1989, 30, 6491. (b)
Fukuyama, T.; Xu, L.; Goto, S. J. Am. Chem. Soc. 1992, 114, 383.
(6) McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115,
6094. (b) Schkeryantz, J. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1995,
117, 4722.
Figure 1.
cross-linking agent in a manner similar to that of mitomycin
C (3).3 In addition to the promising antitumor activity, its
densely functionalized structure with a unique hydroxylamine
hemiacetal has attracted a great deal of attention from
synthetic chemists. Although numerous approaches have been
10.1021/ol016243t CCC: $20.00 © 2001 American Chemical Society
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synthesis of FR-900482. Herein, we report a strategy
involving an intramolecular 1,3-dipolar cycloaddition of a
highly functionalized nitrile oxide.
Scheme 2a
The initial synthetic plan is outlined in Scheme 1. Our
approach involved an intramolecular 1,3-dipolar cycloaddi-
tion of nitrile oxide D to construct the eight-membered
benzazocine C. Reductive opening of the isoxazoline would
lead to the benzazocinone intermediate B bearing a hy-
droxymethyl side chain. B would then be converted to the
target compound by transannular hemiacetalization and
formation of the aziridine. D would be prepared in several
steps through Mitsunobu coupling of aniline derivative E
and F, where the latter would be readily obtained from
tartaric acid.
a (a) DEAD, PPh3, benzene, 50 °C, 30 min; (b) TBAF, THF, 45
min, 86% (2 steps); (c) (COCl)2, DMSO, CH2Cl2, -78 °C; Et3N,
rt; (d) NH2OH‚HCl, NaOAc, EtOH, rt, 30 min; (e) aq NaOCl,
CH2Cl2, 0 °C, 10 h, 58% (3 steps).
Scheme 1
membered ring, we then synthesized an advanced substrate
13 and examined its cycloaddition reaction (Scheme 3).
Scheme 3a
First, we carried out a model reaction using a simple
substrate derived from o-aminostyrene derivative 4 (Scheme
2). Mitsunobu reaction of 49 and primary alcohol 510 and
the subsequent four-step sequence involving desilylation,
Swern oxidation, and condensation with hydroxylamine
hydrochloride gave oxime 7. Cycloaddition reaction took
place smoothly by treatment with sodium hypochlorite,
giving the desired eight-membered ring compound 8 as a
2:1 mixture of diastereomers.11
Having demonstrated the feasibility of the intramolecular
cycloaddition of nitrile oxide for the construction of the eight-
a (a) PPh3CH3Br, K2CO3, 1,4-dioxane, H2O, 60 °C, 10 h, 41%;
(b) Zn, AcOH, CH2Cl2; (c) p-NsCl, Py, CH2Cl2, 86% (2 steps); (d)
5, DEAD, PPh3, benzene, 50 °C, 30 min; (e) TBAF, THF, rt, 45
min, 96% (2 steps); (f) (COCl)2, DMSO, CH2Cl2, -78 °C; Et3N;
(g) NH2OH‚HCl, NaOAc, EtOH, rt; (h) aq NaOCl, CH2Cl2 0 °C,
22% (3 steps).
(7) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron 1997,
53, 10229. (b) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh,
T.; Terashima, S. Tetrahedron 1997, 53, 10239. (c) Katoh, T.; Nagata, Y.;
Yoshino, T.; Nakatani, S.; Terashima, S. Tetrahedron 1997, 53,10253. (d)
Katoh, T.; Terashima, S. J. Synth. Org. Chem., Jpn. 1997, 55, 946.
(8) Fellows, I. M.; Kaelin, Jr., D. E.; Martin, S. F. J. Am. Chem. Soc.
2000, 122, 10781.
(9) Prepared from o-nitrotoluene in five steps (see Supporting Informa-
tion).
(10) For the preparation, see; Marshall, J. A.; Beaudoin, S. J. Org. Chem.
1994, 59, 6614
(11) After completion of the model study, we learned that Kozikowski
also described a similar approach for the construction of benzazocine, but
any further elaboration of the product has not been reported; see:
Kozikowski, A. P.; Mugrage, B. B. J. Chem. Soc., Chem. Commum. 1988,
198.
Starting from the known benzaldehyde 9,12 sequential
transformations including Wittig methylenation, reduction
of azide, and introduction of a p-nitrobenzenesulfonyl
group,13 furnished o-aminostyrene derivative 11. Oxime 13
(12) Bohme, H.; von Gratz, J. G.; Martin, F.; Matusch, R.; Nehne, J.
Liebigs Ann. Chem. 1980, 394. (b) Fukuyama, T.; Xu, L.; Goto, S. J. Am.
Chem. Soc. 1992, 114, 383.
2576
Org. Lett., Vol. 3, No. 16, 2001

was prepared by the similar protocol used for the model
compound 7 and was treated with sodium hypochlorite.
Unfortunately, the undesired nine-membered ring compound
1514 was obtained as a mixture of diastereomers via the
conformation depicted in 14.
Scheme 5a
At this stage, we examined various substrates to achieve
the desired regiochemistry in the cycloaddition. After numer-
ous attempts, we have found that introduction of the
carboethoxy group on the terminus of the olefin completely
controlled both regio- and stereochemistry to furnish the
desired eight-membered ring 20 (Scheme 4). The structure
Scheme 4a
a (a) NaBH4, EtOH/THF (1:1), rt, 4 h, 99%; (b) TFAA, Et3N,
CH2Cl2, aq NaHCO3, rt, 82%; (c) Raney-Ni, H2, 5% aq H3BO3/
EtOH (1:5), rt, 62%; (d) NaBH(OAc)3, AcOH/THF (1:10), 0 °C,
30 min; (e) aq NaOH, MeOH, rt, 5 min, 85% (2 steps); (f) NaIO4,
MeCN/H2O (3:2), 0 °C, 10 min; (g) NaBH4, MeOH, rt, 10 min,
75% (2 steps); (h) TBSCl, Et3N, DMAP, CH2Cl2, rt, 2 h, 70%; (i)
MCPBA, CH2Cl2, 0 °C, 5 min; (j) Ac2O, rt, 1 h, 65% (2 steps); (k)
Dess-Martin periodinane, CH2Cl2, rt, 5 min, 95%.
sis. The resultant triol was treated with NaIO4, and the
aldehyde formed was immediately reduced to give diol 23.
Scheme 6a
a (a) EtO2CCHdPPh3, EtOH, rt, 20 min, 96%; (b) Zn, AcOH,
CH2Cl2, rt, 30 min, 93%; (c) p-NsCl, Py, CH2Cl2, rt, 15 h, 87%;
(d) 5, DEAD, PPh3, benzene, 50 °C, 30 min, 93%; (e) TBAF, THF,
rt, 45 min, 95%; (f) (COCl)2, DMSO, CH2Cl2, -78 °C; Et3N; (g)
NH2OH‚HCl, NaOAc, EtOH, rt, 30 min; (h) aq NaOCl, CH2Cl2, 0
°C, 4 h, 57% (3 steps); (i) PhSH, Cs2CO3, MeCN, 50 °C, 30 min,
74%.
of the cycloadduct 20 was unequivocally established by
X-ray crystallography. Although the stereochemistry at C(7)
was found to be opposite to that required for FR-900482,
switching the starting L-tartrate to D-tartrate could allow us
to set up the correct stereochemistry.
Having successfully constructed the eight-membered ring,
we then converted the cycloadduct 21 to the benzazocinone
key intermediate 24 (Scheme 5). After reduction of the ethyl
ester and protection of the amine as trifluoroacetamide,
isoxazoline was reductively cleaved to give â,γ-dihydroxy-
ketone 22. Ketone 22 was reduced stereoselectively with
NaBH(OAc)3, and the TFA group was removed by hydroly-
a (a) NH2NH2‚H2O, CH2Cl2-MeOH (1:1), rt, 10 min, 78%; (b)
TBAF, AcOH, THF, rt, 2 h, 98%; (c) Amberlist 15E, MeOH, rt, 5
min; (d) Me2C(OMe)2, CH2dC(OMe)Me, PPTS, DMF, 0 °C, 30
min, 78% (2 steps); (e) TESCl, Et3N, DMAP, CH2Cl2, rt, 1 h, 75%;
(f) MsCl, Et3N, CH2Cl2, 0 °C, 20 min, 92%; (g) TBAF, THF, rt, 5
min, 95%; (h) NaH, DMF/THF (1:3), 60 °C, 5 min, 80%; (i) LiN3,
DMF, 100 °C, 82%; (j) MsCl, Et3N, CH2Cl2, rt, 15 min, 79%; (k)
TFA, CH2Cl2, 91%; (l) CO(OCCl3)2, Py, CH2Cl2, 0 °C, 75%; (m)
PPh3, i-Pr2NEt, H2O-THF (1:10), 70%; (n) NH3, CH2Cl2, 75%.
(13) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831.
(14) The structure of the nine-membered ring product was confirmed
by extensive NMR studies.
Org. Lett., Vol. 3, No. 16, 2001
2577

Selective protection of the primary alcohol as a TBS ether,
followed by MCPBA oxidation of the secondary amine gave
N-hydroxylamine. After conversion of the hydroxylamine to
its acetate, the secondary alcohol was oxidized with Dess-
Martin periodinane to furnish the key intermediate 24.
Table 1. Cytotoxicity of FR-900482 Analogues 31 and 32,
FR-900482, and FK317 against U937 Human Leukemia Cells
With the key intermediate 24 in hand, the stage was set
for the formation of the hemiacetal and epoxide. Upon
treatment with hydrazine, acetate 24 gave directly the desired
hemiacetal 25. After deprotection of the TBS group and the
acetonide, the resultant tetraol was subjected to the acetonide
formation conditions to give the desired 1,2-diol 26 as a
single isomer. Construction of epoxide 28 possessing the
desired stereochemistry was realized by the four-step se-
quence involving TES ether formation of the less-hindered
hydroxyl group.
31
32
FR-900482
0.12
FK317
0.0058
IC50 (µg/mL)
0.23
60
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research on Priority Areas (A)
(13029022) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan. The authors thank Dr. Y.
Naoe of Fujisawa Pharmaceutical Co. for determination of
the cytotoxicity.
For the conversion of pentacyclic epoxide 28 to FR-
900482 analogue 31, we adopted the sequence of reactions
developed in our racemic total synthesis of FR-900482.5b
Thus, the epoxide 28 was opened with LiN3, and the resultant
alcohol was converted to mesylate 29. After conversion of
the acetonide to the corresponding carbonate, the azide was
reduced with water/triphenylphoshine to give aziridine 30.
Finally, ammonolysis of the cyclic carbonate provide the FR-
900482 analogue 31 (Table 1).15
Supporting Information Available: Experimental pro-
cedures and spectral data for key compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL016243T
(15) In a preliminary study, compound 31 and epoxide 32, readily
synthesized from 28 (TFA, CH2Cl2, 49%; triphosgene, pyridine, CH2Cl2,
62%; NH3, CH2Cl2, 79%), were tested for their cytotoxicity using U937
human leukemia cell line (see Table 1). Despite the unnatural stereochem-
istry at C(7) and the aziridine, compound 31 displayed the same level of
potency as FR-900482 does. This is an interesting result since the enantiomer
of 1 possesses 100-fold less potent activity than natural 1.7d Epoxide 32,
on the other hand, showed weak cytotoxicity.
In summary, we have accomplished an enatioselective
synthesis of FR-900482 analogues featuring intramolecular
1,3-dipolar cycloaddition of highly functionalized nitrile
oxide with complete stereo- and regioselectivity. The present
synthetic route may be amenable to the synthesis of FR-
900482 and its stereoisomers, as well as a variety of its
analogues. Synthesis of various FR-900482 derivatives
utilizing this strategy and their structure-activity relation-
ships are currently under investigation in our laboratories.
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Org. Lett., Vol. 3, No. 16, 2001