activity in human clinical trials. FK317 is now in advanced
human clinical trials in Japan6 and holds significant promise
for replacing the structurally related and widely used
antitumor drug mitomycin C (MMC, 6).8 Additionally,
FK317 does not induce vascular leak syndrome, a serious
side effect that precipitated the withdrawal of FK973 (3) from
development.6
Natural products FR900482 and FR-66979 (and by anal-
ogy, FK973 and FK317) have been demonstrated to be
activated by a two-electron reduction of the N-O bond9 to
give the intermediate ketone 7, which is in equilibrium with
carbinolamine 8 (Scheme 1). Elimination of water and
cytotoxic activity and the capacity to mediate interstrand
cross-link formation.6b
Our laboratory has focused on the design and synthesis12,13
of pro-mitosenes that are activated by alternative chemical
signals to the obligate reductive activation pathway necessary
for FR900482 and congeners.14 The Fujisawa series drugs
and MMC all function at the limit of endogenous reducing
equivalents in the hypoxic environment of the tumor.
Synthesis of masked mitosene progenitors with the general
structure 11 was envisioned to afford opportunities for the
efficient, controlled release of the highly reactive, bis-
electrophilic mitosene that should be useful for improving
the potency and selectivity of this family of agents. Efforts
toward this approach have been previously reported14 that
demonstrated the viability of accessing a mitosene core from
a structure similar to 11 but lacked the second electrophilic
site (the carbamoylmethyl residue at C-13). We describe here
the synthesis of a fully functional masked mitosene progeni-
tor based on structure 11 that cross-links DNA upon
photochemical activation at concentrations down to 1.0 µM.
Optically active aziridine 13, prepared as previously
described,14,15 was condensed with 12 in the presence of
sodium methoxide to afford the secondary alcohol 14 in 90%
yield as a mixture of epimers (Scheme 2).14 Protection with
diethylisopropylsilyl chloride (DEIPSCl) followed by oxida-
tive removal of the para-methoxybenzyl ether afforded 15
in 72% yield.
Scheme 1
Dess-Martin oxidation16 afforded aldehyde 16 in 90%
yield. Reduction of the nitro function by catalytic hydrogena-
tion and subsequent cyclization of the amino aldehyde to
the eight-membered ring substance under dilute conditions
(∼1.0 mM) was effected with MgSO4 and 4 Å sieves
furnishing the corresponding cyclic imine. Reduction of the
imine with NaCNBH3 and AcOH gave 17 in 55∼75% yield.
(11) (a) Woo, J.; Sigurdsson, S. T.; Hopkins, P. B. J. Am. Chem. Soc.
1993, 115, 1199. (b) Huang, H.; Pratum, T. K.; Hopkins, P. B. J. Am. Chem.
Soc. 1994, 116, 2703. (c) Paz, M. M.; Hopkins, P. B. Tetrahedron Lett.
1997, 38, 343∼346. (d) Paz, M. M.; Hopkins, P. B. J. Am. Chem. Soc.
1997, 119, 5999.
(12) For synthetic approaches to FR900482, see: (a) Yasuda, N.;
Williams, R. M. Tetrahedron Lett. 1989, 30, 3397. (b) Jones, R. J.; Rapoport,
H. J. Org. Chem. 1990, 55, 1144. (c) Martin, S. F.; Wagman, A. S.
Tetrahedron Lett. 1995, 36, 1169. (d) Miller, S. J.; Kim, S.-H.; Chen, Z.-
R.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 2108. (e) Lim, H.-J.;
Sulikowski, G. A. Tetrahedron Lett. 1996, 37, 5243. (f) Ziegler, F. E.;
Belema, M.; J. Org. Chem. 1997, 62, 1083. (g) Mithani, S.; Drew, D. M.;
Rydberg, E. H.; Taylor, N. J.; Mooibroek, S.; Dmitrienko, G. I. J. Am.
Chem. Soc. 1997, 119, 1159. (h) Zhang, W.; Wang, C.; Jimenez, L. S. Synth.
Commun. 2000, 30, 351. (i) Kambe, M.; Arai, E.; Suzuki, M.; Tokuyama,
H.; Fukuyama, T. Org. Lett. 2001, 3, 2575.
tautomerization culminates in the production of the reactive
mitosene species 9, which preferentially cross-links duplex
5′
DNA at CpG′3 steps in the minor groove.10,11 It should be
(13) Total syntheses of FR900482 have been reported by three groups;
see: (a) Fukuyama, T.; Xu, L.; Goto, S. J. Am. Chem. Soc. 1992, 114, 383.
(b) Schkeryantz, J. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117,
4722. (c) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron Lett.
1996, 37, 3471. (d) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh,
T.; Terashima, S. Tetrahedron Lett. 1996, 37, 3475. (e) Katoh, T.; Yoshino,
T.; Nagata, Y.; Nakatani, S.; Terashima, S. Tetrahedron Lett. 1996, 37,
3479. (f) A formal synthesis has also been reported: Fellows, I. M.; Kaelin,
D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781. (g) In addition,
we have recently completed an enantioselective synthesis of FR900482 and
FR66979: Judd, T. C.; Williams, R. M. Unpublished results.
(14) (a) Rollins, S. B.; Williams, R. M. Tetrahedron Lett. 1997, 38, 4033.
(b) Rollins, S. B.; Judd, T. C.; Williams, R. M. Tetrahedron 2000, 56, 521.
(15) Spada, M. R.; Ubukata, M.; Isono, K. Heterocycles 1992, 34, 1147.
(16) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Ireland,
R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
noted that the semisynthetic derivatives FK317 and FK973
must be monodeacetylated in vitro and in vivo to display
(7) (a) Masuda, K.; Nakamura, T.; Mizota, T.; Mori, J.; Shimomura, K.
Cancer Res. 1988, 48, 5172. (b) Masuda, K.; Nakamura, T.; Shimomura,
K. J. Antibiotics 1988, 41, 1497.
(8) (a) Tomasz, M.; Lipman, R.; Chowdary, D.; Pawlak, J.; Verdine, G.
L.; Nakanishi, K. Science 1987, 235, 1204. (b) Tomasz, M. Chem. Biol.
1995, 2, 575-579 and references therein.
(9) Fukuyama, T.; Goto, S. Tetrahedron Lett. 1989, 30, 6491.
(10) (a) Williams, R. M.; Rajski, S. R. Tetrahedron Lett. 1992, 33, 2929.
(b) Williams, R M.; Rajski, S. R. Tetrahedron Lett. 1993, 34, 7023. (c)
Huang, H.; Rajski, S. R.; Williams, R. M.; Hopkins, P. B. Tetrahedron
Lett. 1994, 35, 9669. (d) Williams, R. M.; Rajski, S. R.; Rollins, S. B.
Chem. Biol. 1997, 4, 127. (e) Rajski, S. R.; Rollins, S. B.; Williams, R. M.
J. Am. Chem. Soc. 1998, 120, 2192.
3712
Org. Lett., Vol. 4, No. 21, 2002