‡ Selected data for 9: dH(360 MHz, DMSO-d6) 10.35 (s, 1H), 10.30 (s, 1H),
10.18 (s, 1H), 9.90 (s, 1H), 9.86 (s, 1H), 9.75 (s, 1H), 9.62 (s,1H), 9.59 (s,
1H), 8.55 (d, 1H, J 2.0, C6-H), 7.97 (s, 1H, C4-H), 7.86 (dd, 1H, J 2.0, 7.5,
C8-H), 7.74 (d, 1H, J 7.5, C9-H), 7.64 (s, 1H, Im-H), 7.60 (s, 1H, Im-H),
7.51 (s, 1H, Im-H), 3.31 (d, 1H, J 1.5, Py-H), 7.24 (d, 1H, J 1.5, Py-H), 7.21
(d, 1H, J 1.5, Py-H), 7.16 (d, 1H, J 1.5, Py-H), 7.07 (d, 1H, J 1.5, Py-H), 6.88
(d, 1H, J 1.5, Py-H), 4.7–3.6 (m, 23H, NCH3, ClCH2, C1-H, C2-H), 2.28 (t,
2H, J 7.3, COCH2), 2.20 (t, 2H, J 7.4, COCH2), 1.63–1.53 (m, 4H,
COCH2CH2), 0.91–0.86 (m, 6H, COCH2CH2CH3); Calc. for
describe the synthesis of an unsymmetrical bis-lexitropsin–CBI
conjugate, which contains two different lexitropsins. In our
previous work,6 the CBI moiety was obtained by an in situ
primary radical trap with TEMPO. Here, the CBI moiety was
synthesized by using a more concise and shorter route which
was recently developed by Patel and co-workers.8
Deprotonation of carbamate 16 using NaH, followed by
alkylation of the resulting anion with 1,3-dichloropropene in the
presence of the phase transfer catalyst Bu4NI gave an mixture of
Z and E isomers of vinyl chloride 2. Selective reduction of the
nitro group of 2 using hydrazine,9 followed by protection of the
amino group, provided 3, the desired precursor for the
intramolecular aryl radical cyclization on to a tethered vinyl
chloride.8 A deoxygenated solution of 3 in dry benzene was
heated at reflux for 15 h in the presence of 2 equiv. of Bu3SnH
and a catalytic amount of AIBN to give the fully protected
bifunctionalized CBI prodrug form, racemic 4.† Although not
investigated in detail, no reaction occurred when nitro com-
pound 2 was treated under the same conditions as amine 3.
Detachment10 of the Fmoc group from 4, followed by
coupling with polypyrrole carboxamide 511 using HOBt and
EDCI as the coupling agents11b,c afforded the hybrid 6.
Hydrogenolysis8a of 6 served to remove the benzyl ether almost
quantitatively and provided 7. Acid-mediated deprotection of 7,
followed by coupling with polyimidazole carboxamide 811
using EDCI provided the final bis-lexitropsin–CBI precursor
conjugate 9‡ in fair yield.
In summary, we have described a synthesis of the bis-
functionalized CBI precursor containing two different pro-
tective groups and obtained the corresponding unsymmetrical
bis-lexitropsin conjugate. Results on the DNA sequence
preferences and biological evaluation will be reported in due
course.
We are grateful for a research grant (to J. W. L.) from the
Natural Sciences and Engineering Research Council of Can-
ada.
C
54H58N17O9Cl: C, 57.15; N, 21.17. Found C, 57.06; N, 20.97%.
1 L. J. Hanka, A. Dietz, S. A. Gerpheide, S. L. Kuentzel and D. G. Martin,
J. Antibiot., 1978, 31, 1211.
2 B. K. Bhuyan, K. A. Newell, S. L. Crampton and D. D. Von Hoff,
Cancer Res., 1982, 42, 3532.
3 H. Iida and J. W. Lown, Recent Res. Dev. Synth. Org. Chem., 1998, 1,
17 and references cited therein.
4 D. L. Boger and R. S. Coleman, J. Am. Chem. Soc, 1988, 110, 4796;
C. H. Lin, D. Sun and L. H. Hurley, Chem. Res. Toxicol., 1991, 4, 21;
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Chem., Int. Ed. Engl., 1996, 35, 1439.
5 D. L. Boger, T. Ishizaki, R. J. Wysocki, Jr., S. A. Munk, P. A. Kitos and
O. Suntornwat, J. Am. Chem. Soc., 1989, 111, 6461; D. L. Boger and T.
Ishizaki, J. Org. Chem., 1990, 55, 5823; D. L. Boger, W. Yun and B. R.
Teegarden, J. Org. Chem., 1992, 57, 2873; D. L. Boger, P. Mesini and
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6 G. Jia, H. Iida and J. W. Lown, Heterocycl. Commun., 1998, in the
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7 K. E. Rao and J. W. Lown, Trends Org. Chem., 1992, 3, 141 and
references cited therein.
8 (a) V. F. Patel, S. L. Andis, J. K. Enkema, D. A. Johnson, J. H. Kennedy,
F. Mohamadi, R. M. Schultz, D. J. Soose and M. M. Spees, J. Org.
Chem., 1997, 62, 8868; (b) D. L. Boger, C. W. Boyce, R. M. Garbaccio
and M. Searcey, Tetrahedron Lett., 1998, 39, 2227.
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1339.
Notes and references
10 M. Ueki and M. Amemiya, Tetrahedron Lett., 1987, 28, 6617.
11 (a) E. Nishiwaki, S. Tanaka, H. Lee and M. Shibuya, Heterocycles,
1988, 27, 1945; (b) L. Huang, J. C. Quada, Jr. and J. W. Lown,
Bioconjugate Chem., 1995, 6, 21; (c) R. Zhao, N. H. Al-Said, D. L.
Sternbach and J. W. Lown, J. Med. Chem., 1997, 40, 216.
† Selected data for 4: dH(360 MHz, acetone-d6) 9.02 (s, NH ), 8.38 (s, 1H,
C6-H), 7.88–7.30 (m, 16H, Ar-H), 5.30 (s, 2H, PhCH2O), 4.50 (d, 2H, J 6.9,
CH2 in Fmoc), 4.30 (t, 1H, J 6.9, CH in Fmoc), 4.22–4.05 (m, 3H, C1-H,
C2-H), 4.01 (dd, 1H, J 3.1, 11.1, CHHCl), 3.70 (dd, 1H, J 8.4,11.0, CHHCl),
1.58 (s, 9H, Boc-H); Calc. for C40H37N2O5Cl: C, 72.66; H, 5.64; N, 4.24.
Found C, 72.55; H, 5.74; N, 4.20%.
Communication 8/07884J
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Chem. Commun., 1999, 119–120