Synthesis and X-ray analysis of an unprecedented and stable 2-aza-4,4-spirocyclopropacyclohexadienone

Article abstract of DOI:10.1021/ol035000t

(Matrix presented) An efficient eight-step synthesis (54% overall) and the subsequent X-ray characterization of 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]-3-azaindol-4-one (CBA) containing an aza variant of the CC-1065/duocarmycin alkylation subunit are deta

Full text of DOI:10.1021/ol035000t

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2577-2579
Synthesis and X-ray Analysis of an
Unprecedented and Stable
2-Aza-4,4-spirocyclopropacyclohexadienone
Jay P. Parrish, David B. Kastrinsky, and Dale L. Boger*
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
boger@scripps.edu
Received June 4, 2003
ABSTRACT
An efficient eight-step synthesis (54% overall) and the subsequent X-ray characterization of 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]-3-azaindol-
4-one (CBA) containing an aza variant of the CC-1065/duocarmycin alkylation subunit are detailed. Despite the unique deep-seated aza modification
providing an unprecedented and stable 2-aza-4,4-spirocyclopropacyclohexadienone, CBA proved to be structurally identical with CBI, the
carbon analogue, in terms of the stereoelectronic alignment of the key cyclopropane, its bond lengths, and the length of the diagnostic
C3a−N2 bond reflecting the extent of vinylogous amide conjugation.
CC-1065 (1)1 and the duocarmycins (2 and 3)2,3 are the parent
members of a class of potent antitumor antibiotics4 that derive
their properties through a sequence-selective alkylation of
duplex DNA (Figure 1).5,6 Since their disclosure, an extensive
series of studies have characterized the structural features
responsible for or important to the DNA alkylation reaction
and established fundamental relationships between structure
and reactivity or structure and activity.5-10 Aside from the
structural complexity inherent in the alkylation subunit, they
possess an uncharacteristic stability that defies intuition. This
is due principally to the vinylogous amide conjugation with
and stabilization of the cyclohexadienone structure, which
is dominant over that activating the cross-conjugated cyclo-
propane.11-13 Accordingly, disruption of this vinylogous
amide conjugation leads to remarkable increases in reactivity
as large as 104-fold,13 which we have suggested is the source
of catalysis for the DNA alkylation reaction.7-11
The synthesis of analogues containing deep-seated struc-
tural changes, including those within the intricate alkylation
subunit, have been central to these studies, providing insight
not accessible through examination of the natural products.14
Among those introduced, the 1,2,9,9a-tetrahydrocyclopropa-
(1) Chidester, C. G.; Krueger, W. C.; Mizsak, S. A.; Duchamp, D. J.;
Martin, D. G. J. Am. Chem. Soc. 1981, 103, 7629.
(2) Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano,
K.; Kawamoto, I.; Tomita, F.; Nakano, H. J. Antibiot. 1988, 41, 1915.
(3) Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.; Kawamoto,
I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. J. Antibiot. 1990, 43, 1037.
(4) Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.; Ogawa, T.;
Takahashi, K.; Sano, H.; Saitoh, Y. Chem. Pharm. Bull. 1995, 43, 378.
(5) Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed. Engl. 1996, 35,
1438. For earlier reviews, see: Boger, D. L. Acc. Chem. Res. 1995, 28, 20.
Boger, D. L.; Johnson, D. S. Proc. Natl. Acad. Sci., U.S.A. 1995, 92, 3642.
Boger, D. L. Chemtracts: Org. Chem. 1991, 4, 329.
(6) Warpehoski, M. A.; Hurley, L. H. Chem. Res. Toxicol. 1988, 1, 315.
(7) Boger, D. L.; Garbaccio, R. M. Bioorg. Med. Chem. 1997, 5, 263.
(8) Boger, D. L.; Garbaccio, R. M. Acc. Chem. Res. 1999, 32, 1043.
(9) Wolkenberg, S. W.; Boger, D. L. Chem. ReV. 2002, 102, 2477.
(10) Ambroise, Y.; Boger, D. L. Bioorg. Med. Chem. Lett. 2002, 12,
303.
(11) Boger, D. L.; Bollinger, B.; Hertzog, D. L.; Johnson, D. S.; Cai,
H.; Mesini, P.; Garbaccio, R. M.; Jin, Q.; Kitos, P. A. J. Am. Chem. Soc.
1997, 119, 4987.
(12) Boger, D. L.; Hertzog, D. L.; Bollinger, B.; Johnson, D. S.; Cai,
H.; Goldberg, J.; Turnbull, P. J. Am. Chem. Soc. 1997, 119, 4977.
(13) Boger, D. L.; Turnbull, P. J. Org. Chem. 1997, 62, 5849. Boger,
D. L.; Turnbull, P. J. Org. Chem. 1998, 63, 8004. CSD NILJUN for
N-CO2Me-CBI.
(14) Review: Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg,
J. Chem. ReV. 1997, 97, 787.
10.1021/ol035000t CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/17/2003

[e]-3-azaindol-4-one (CBA, 6) alkylation subunit. Although
7 was anticipated to be even more stable than the CBI deriv-
ative 5, the properties of 6, incorporating an unprecedented
2-aza-4,4-spirocyclopropacyclohexadienone, were unknown.
Herein, we report the first synthesis and structural charac-
terization of this unique, and surprisingly stable, system.
The synthesis of the CBA subunit began by treatment of
8 under conditions disclosed to effect formation of 1-bromo-
3-aminoisoquinoline (Scheme 1).16 Nucleophilic introduction
Scheme 1
Figure 1.
[c]benz[e]indol-4-one (CBI) alkylation subunit has emerged
as the most extensively examined, extended, and modified
series (Figure 2).15 Not only is CBI the most synthetically
of the C1 benzyloxy group and subsequent Boc protection
of the resulting amine provided 9 in 59% over two steps.
Regioselective C4 iodination and N-alkylation with 1,3-
dichloropropene to give 10 set the stage for a key 5-exo-trig
aryl radical-alkene cyclization to form 11.17 Resolution of
11 by chromatographic separation on a semiprep Chiralcel
OD column cleanly provided both enantiomers, which were
then subjected to hydrogenolysis to provide 12 ((R)-enan-
tiomer not shown).18,19 Spirocyclization of 12 was effected
by treatment with DBU in anhydrous CH3CN to give N-Boc-
CBA (13) in superb yield (95%) in eight steps and 54%
overall yield. Additionally, treatment of 12 with HCl and
subsequent spirocyclization afforded CBA (14). Likewise,
Figure 2.
accessible alkylation subunit in a rich series, but its deriva-
tives exhibit a potency and efficacy that surpass those of 1
and 2 and approach those of 3, and it exhibits a stability
and inherent reaction regioselectivity that are near optimal.15
An unusual characteristic of this class of compounds is
that the cyclopropane precursors such as 5 readily close in
vitro and in vivo, displaying biological properties that are
not distinguishable from the final cyclopropane-containing
compounds, yet stand up to prolonged storage more ef-
fectively. In our examination of modified alkylation subunits,
we targeted the pyridone 7 as an especially storage stable
precursor to the unique 1,2,9,9a-tetrahydrocyclopropa[c]benz-
(16) Johnson, F.; Nasutavicus, W. A. J. Org. Chem. 1962, 27, 3953.
(17) Patel, V. F.; Andis, S. L.; Enkema, J. K.; Johnson, D. A.; Kennedy,
J. H.; Mohamadi, F.; Schultz, R. M.; Soose, D. J.; Spees, M. M. J. Org.
Chem. 1997, 62, 8868. Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.;
Searcey, M. Tetrahedron Lett. 1998, 39, 2227.
(18) Resolution was performed at this stage due to optimum solubility.
Separation of the enantiomers of 12 is also possible (R ) 1.17).
(19) Boger, D. L.; Yun, W. J. Am. Chem. Soc. 1994, 116, 7996.
(15) Boger, D. L.; Ishizaki, T.; Kitos, P. A.; Suntornwat, O. J. Org. Chem.
1990, 55, 5823. Parrish, J. P.; Kastrinsky, D. B.; Stauffer, F.; Hedrick, M.
P.; Hwang, I.; Boger, D. L. Bioorg. Med. Chem. 2003, 11, in press, and
refs cited therein. Drost, K. J.; Cava, M. P. J. Org. Chem. 1991, 56, 2240.
Aristoff, P. A.; Johnson, P. D. J. Org. Chem. 1992, 57, 6234.
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Org. Lett., Vol. 5, No. 14, 2003

acid treatment of 12 and subsequent coupling of the amine
hydrochloride salt with 5,6,7-trimethoxyindole-2-carboxylic
acid19 (TMI) provided 15, which could be spirocyclized to
16 using DBU.
With crystalline 13 in hand, its single-crystal X-ray
structure determination20 was conducted on needles obtained
by recrystallization from 9:1 hexanes-CH2Cl2. Not only are
its overall structural characteristics identical to those of
N-CO2Me-CBI,13 including the stereoelectronic alignment of
the key cyclopropane (Figure 3), but the two structures are
nearly superimposable. Remarkably, essentially all bond
lengths of N-Boc-CBA were within (0.02 Å of those of
N-CO2Me-CBI, including not only all three cyclopropane
bonds, of which the reacting C8b-C9 bonds are identical
(1.544 vs 1.544 Å), but also the C3a-N2 bond (1.383 vs
1.390 Å, respectively), whose length is diagnostic of the
extent of vinylogous amide conjugation.7,8 The only excep-
tions are the slightly more perturbed C3a-N3 vs C3a-C3
bond (1.30 vs 1.35 Å) and the adjacent N3-C4 vs C3-C4
bond (1.40 vs 1.44 Å) reflecting the intrinsically shorter
CdN vs CdC bond lengths. The unusual stability of 13 and
its 2-aza-4,4-spirocyclopropacyclohexadienone may be at-
tributed to the geometrical constraints of the fused five-
membered ring that prevents the ideal, bisected conjugation
of the cyclopropane with the π-system13 and, most impor-
tantly, the N2 amidine cross-conjugation.
Thus, the structural characteristics and intrinsic chemical
stability of CBA suggest that it may serve as an additional
stable alternative to CBI and the related naturally occurring
DNA alkylation subunits. The full characterization of the
chemical and biological properties of the CBA-based com-
pounds is in progress and will be reported in due course.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of NIH (CA41986) and the Skaggs Institute
for Chemical Biology. We especially thank Dr. R. Chadha
for the X-ray structure determination and H. Schmitt for
initial studies. D.B.K. is a Skaggs Fellow.
Supporting Information Available: Full experimental
details for the preparation of 9-16 and X-ray bond length
comparisons of 13 with N-CO2Me-CBI. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL035000T
(20) Atomic coordinates for 13 have been deposited with the Cambridge
Crystallographic Data Centre under deposition number CDCC 209699.
(21) Comparison figure is provided in Supporting Information.
Figure 3. X-ray analysis
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