Asymmetric synthesis of 1,2,9,9a-tetrahydrocyclopropa[ c ]benzo[ e ]indol-4-one (CBI)

Article abstract of DOI:10.1021/jo102136w

A short, asymmetric synthesis of the 1,2,9,9a-tetrahydrocyclopropa[c] benzo[e]indol-4-one (CBI) analogue of the CC-1065 and duocarmycin DNA alkylation subunits is described. Treatment of iodo-epoxide 5, prepared by late-stage alkylation of 4 with (S)-glyc

Full text of DOI:10.1021/jo102136w

pubs.acs.org/joc
Asymmetric Synthesis of 1,2,9,9a-Tetrahydrocyclopropa[c]benzo[e]indol-
4-one (CBI)
James P. Lajiness and Dale L. Boger*
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
boger@scripps.edu
Received October 27, 2010
A short, asymmetric synthesis of the 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI)
analogue of the CC-1065 and duocarmycin DNA alkylation subunits is described. Treatment of
iodo-epoxide 5, prepared by late-stage alkylation of 4 with (S)-glycidal-3-nosylate, with EtMgBr at
room temperature directly provides the optically pure alcohol 6 in 87% yield (99% ee) derived from
selective metal-halogen exchange and subsequent regioselective intramolecular 6-endo-tet cycliza-
tion. The use of MeMgBr or i-PrMgBr also provides the product in high yields (82-87%), but
requires larger amounts of the Grignard reagent to effect metal-halogen exchange and cyclization.
Direct transannular spirocyclization of 7 following O-debenzylation of 6 provides N-Boc-CBI. This
approach represents the most efficient (9-steps, 31% overall) and effective (99% ee) route to the
optically pure CBI alkylation subunit yet described.
Introduction
which is not only synthetically more accessible but was found
to possess a number of features that have made its use more
attractive than the natural alkylation subunits themselves.
Most significantly, its derivative analogues were found to
be 4-fold more stable and 4-fold more potent than the
CC-1065 (1)1 and duocarmycin SA (2)2 represent the key
members of a class of naturally occurring antitumor agents
that also includes duocarmycin A3 and yatakemycin4 that
derive their biological activity from their ability to selectively
alkylate duplex DNA (Figure 1).5,6 The study of the natural
products, their synthetic unnatural enantiomers,7 deriva-
tives, and key analogues has defined the fundamental fea-
tures that control the DNA alkylation selectivity, efficiency,
and catalysis, providing a detailed understanding of the
relationships between structure, reactivity, and biological
properties.6
(5) For duocarmycin SA, see: (a) Boger, D. L.; Johnson, D. S.; Yun, W. J.
Am. Chem. Soc. 1994, 116, 1635. For yatakemycin, see: (b) Parrish, J. P.;
Kastrinsky, D. B.; Wolkenberg, S. E.; Igarashi, Y.; Boger, D. L. J. Am.
Chem. Soc. 2003, 125, 10971. (c) Trzupek, J. D.; Gottesfeld, J. M.; Boger,
D. L. Nat. Chem. Biol. 2006, 2, 79. (d) Tichenor, M. S.; MacMillan, K. S.;
Trzupek, J. D.; Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2007,
129, 10858. For CC-1065, see: (e) Hurley, L. H.; Lee, C.-S.; McGovren, J. P.;
Warpehoski, M. A.; Mitchell, M. A.; Kelly, R. C.; Aristoff, P. A. Biochem-
istry 1988, 27, 3886. (f) Hurley, L. H.; Warpehoski, M. A.; Lee, C.-S.;
McGovren, J. P.; Scahill, T. A.; Kelly, R. C.; Mitchell, M. A.; Wicnienski,
N. A.; Gebhard, I.; Johnson, P. D.; Bradford, V. S. J. Am. Chem. Soc. 1990,
112, 4633. (g) Boger, D. L.; Johnson, D. S.; Yun, W.; Tarby, C. M. Bioorg.
Med. Chem. 1994, 2, 115. (h) Boger, D. L.; Coleman, R. S.; Invergo, B. J.;
Sakya, S. M.; Ishizaki, T.; Munk, S. A.; Zarrinmayeh, H.; Kitos, P. A.;
Thompson, S. C. J. Am. Chem. Soc. 1990, 112, 4623. For duocarmycin A,
see: (i) Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Munk, S. A.; Kitos, P. A.;
Suntornwat, O. J. Am. Chem. Soc. 1990, 112, 8961. (j) Boger, D. L.; Ishizaki,
T.; Zarrinmayeh, H. J. Am. Chem. Soc. 1991, 113, 6645. (k) Boger, D. L.;
Yun, W.; Terashima, S.; Fukuda, Y.; Nakatani, K.; Kitos, P. A.; Jin, Q.
Bioorg. Med. Chem. Lett. 1992, 2, 759. (l) Boger, D. L.; Yun, W. J. Am. Chem.
Soc. 1993, 115, 9872. (m) Boger, D. L.; Munk, S. A.; Zarrinmayeh, H.;
Ishizaki, T.; Haught, J.; Bina, M. Tetrahedron 1991, 47, 2661. (n) Boger,
D. L.; Wysocki, R. J.; Ishizaki, T. J. Am. Chem. Soc. 1990, 112, 5230.
Among the earliest and most studied of the natural
product alkylation subunit analogues is CBI8 (Figure 2),
(1) Martin, D. G.; Biles, C.; Gerpheide, S. A.; Hanka, L. J.; Krueger,
W. C.; McGovren, J. P.; Mizsak, S. A.; Neil, G. L.; Stewart, J. C.; Visser, J.
J. Antibiot. 1981, 34, 1119.
(2) Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.; Kawamoto,
I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. J. Antibiot. 1990, 43, 1037.
(3) Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano,
K.; Kawamoto, I.; Tomita, F.; Nakano, H. J. Antibiot. 1988, 41, 1915.
(4) Igarashi, Y.; Futamata, K.; Fujita, T.; Sekine, A.; Senda, H.; Naoki,
H.; Furumai, T. J. Antibiot. 2003, 56, 107.
DOI: 10.1021/jo102136w
r
Published on Web 12/30/2010
J. Org. Chem. 2011, 76, 583–587 583
2010 American Chemical Society

Lajiness and Boger
JOCArticle
FIGURE 1. Natural products.
corresponding analogues bearing the 7-MeCPI subunit
found in CC-1065 and to display a substantially enhanced
intrinsic reaction regioselectivity (>20:1 vs 4-6:1).9 Addi-
tionally, its derivative analogues were found to alkylate
DNA with an unaltered sequence selectivity at enhanced
rates and with a greater efficiency than the corresponding
7-MeCPI analogues.10 Although not quite as potent as the
corresponding duocarmycin SA analogues, the ability to
easily prepare and evaluate CBI analogues designed to probe
fundamental questions on structure, reactivity, and activity
have resulted in its extensive use.6 Thus, it is on this alkyla-
tion subunit analogue that new design concepts are often
explored, developed, and evaluated.
Its subsequent exploration by others and our continued
examination of its properties have provided alternative11 and
(6) Reviews: (a) Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed. Engl.
1996, 35, 1438. (b) Boger, D. L. Acc. Chem. Res. 1995, 28, 20. (c) Boger, D. L.;
Johnson, D. S. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 3642. (d) Boger, D. L.;
Garbaccio, R. M. Acc. Chem. Res. 1999, 32, 1043. (e) Searcey, M. Curr.
Pharm. Des. 2002, 8, 1375. (f) Tichenor, M. S.; Boger, D. L. Nat. Prod. Rep.
2008, 25, 220. (g) MacMillan, K. S.; Boger, D. L. J. Med. Chem. 2009, 52,
5771. (h) Boger, D. L.; Garbaccio, R. M. Bioorg. Med. Chem. 1997, 5, 263.
(7) (a) Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1988, 110, 1321.
(b) Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1988, 110, 4796. (c) Boger,
D. L.; Machiya, K. J. Am. Chem. Soc. 1992, 114, 10056. (d) Boger, D. L.;
Machiya, K.; Hertzog, D. L.; Kitos, P. A.; Holmes, D. J. Am. Chem. Soc. 1993,
115, 9025. (e) Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem. Soc.
1996, 118, 2301. (f) Boger, D. L.;McKie, J. A.;Nishi, T.;Ogiku, T. J. Am. Chem.
Soc. 1997, 119, 311. (g) Tichenor, M. S.; Kastrinsky, D. B.; Boger, D. L. J. Am.
Chem. Soc. 2004, 126, 8346.
(8) (a) Boger, D. L.; Ishizaki, T.; Wysocki, R. J., Jr.; Munk, S. A.; Kitos,
P. A.; Suntornwat, O. J. Am. Chem. Soc. 1989, 111, 6461. (b) Boger, D. L.;
Ishizaki, T.; Kitos, P. A.; Suntornwat, O. J. Org. Chem. 1990, 55, 5823.
(c) Boger, D. L.; Ishizaki, T. Tetrahedron Lett. 1990, 31, 793. (d) Boger, D. L.;
Ishizaki, T.; Zarrinmayeh, H.; Kitos, P. A.; Suntornwat, O. Bioorg. Med.
Chem. Lett. 1991, 1, 55. (e) Boger, D. L.; Ishizaki, T.; Sakya, S. M.; Munk,
S. A.; Kitos, P. A.; Jin, Q.; Besterman, J. M. Bioorg. Med. Chem. Lett. 1991,
1, 115. (f) Boger, D. L.; Munk, S. A.; Ishizaki, T. J. Am. Chem. Soc. 1991, 113,
2779. (g) Boger, D. L.; Yun, W. J. Am. Chem. Soc. 1994, 116, 5523. (h) Boger,
D. L.; Yun, W.; Han, N.; Johnson, D. S. Bioorg. Med. Chem. 1995, 3, 611.
(i) Boger, D. L.; Yun, W.; Cai, H.; Han, N. Bioorg. Med. Chem. 1995, 3, 761.
(j) Boger, D. L.; Yun, W.; Han, N. Bioorg. Med. Chem. 1995, 3, 1429.
(9) (a) Parrish, J. P.; Trzupek, J. D.; Hughes, T. V.; Hwang, I.; Boger,
D. L. Bioorg. Med. Chem. 2004, 12, 5845. (b) Parrish, J. P.; Hughes, T. V.;
Hwang, I. J. Am. Chem. Soc. 2004, 126, 80.
FIGURE 2. Approaches to the asymmetric synthesis of CBI.
iteratively improved syntheses12-15 of CBI. Nonetheless, most
studies detailing its preparation and use rely on a Chiralcel
(10) (a) Boger, D. L.; Munk, S. A. J. Am. Chem. Soc. 1992, 114, 5487. (b)
Boger, D. L.; Munk, S. A.; Ishizaki, T. J. Am. Chem. Soc. 1991, 113, 2779.
(11) Drost, K. J.; Cava, M. P. J. Org. Chem. 1991, 56, 2240.
(13) Boger, D. L.; McKie, J. A. J. Org. Chem. 1995, 60, 1271.
(14) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Searcey, M. Tetra-
hedron Lett. 1998, 39, 2227.
(12) Boger, D. L.; Yun, W.; Teegarden, B. R. J. Org. Chem. 1992, 57,
2873.
(15) Review: Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg,
J. A. Chem. Rev. 1997, 97, 787.
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OD chromatographic resolution16 of a racemic precursor.
Although several approaches to the asymmetric synthesis of
CBI have been reported, none have replaced this or related
chromatographic resolutions.17 The asymmetric approaches
(Figure 2) include our own strategies relying on an asym-
metric hydroboration (73%, 80% ee),18 a Jacobsen epoxida-
tion (60%, 92% ee),18 and a lipase-catalyzed resolution of a
prochiral diol (88%, 99% ee).19 Complementary to these
efforts are Lown’s lipase-catalyzed resolution of 3,20 the use
of a Sharpless AD reaction (30-60%, 70% ee),21 and
Mohamadi’s application of an asymmetric hydroboration
reaction (58%, 40% ee).22 The unusual and structure-depen-
dent activity of the unnatural as well as natural enantiomers
with this class of natural products requires the evaluation of
enantiomers of unusually high optical purities.23 Thus, even
small amounts of natural enantiomer contaminant (<1%)
in the unnatural enantiomer samples can provide skewed
biological results, requiring the use of a route or technique
that delivers the agents in g99% ee. In the course of our
recent development of a unique class of reductively activated
CBI-based prodrugs,24,25 we have explored and herein report
an effective approach to the asymmetric synthesis of CBI.
Recently, we described the asymmetric total synthesis of
(þ)- and ent-(-)-yatakemycin and (þ)- and ent-(-)-duocar-
mycin SA through use of a selective metal-halogen
exchange and subsequent intramolecular regioselective
6-endo-tet epoxide opening for the late-stage introduction
of the chirality, simplifying access to either enantiomer.26
Thus, treatment of the aryl iodide with i-PrMgCl (1.1 equiv
of i-PrMgCl, -42 °C, 1 h) followed by transmetalation to
the cuprate (0.2 equiv of CuI-PBu3, -78 °C, 2 h) provided
the desired alcohol in 69% yield and 99% ee (eq 1). Herein,
we report the extension of this approach to the asymmetric
synthesis of the CBI alkylation subunit, representing the
most efficient (9-steps, 31% overall) and effective (99% ee)
synthesis to date.
SCHEME 1
nosylate27 (1.3 equiv, 1.5 equiv of NaH, DMF, 0 to 23 °C, 3 h,
90%) provided 5 with clean SN2 displacement of the nosylate
versus epoxide opening and subsequent displacement of the
nosylate (Scheme 1). Competitive epoxide opening would
provide the enantiomeric epoxide, degrading the enantio-
meric purity of the product. However, the product 5 is
isolated in nearly perfect optical purity, confirming and esta-
blishing the regioselectivity of the alkylation. Initial attempts
to afford the aryl Grignard by metal-halogen exchange with
i-PrMgCl analogous to our efforts on yatakemycin only pro-
vided recovered starting material, even at elevated reaction
temperatures (23 °C) and extended reaction times (72 h),
presumably due to the use of a more electron-rich aryl iodide
inherent in the naphthalene vs electron-deficient indole sub-
strate. Thus, the more electron-rich naphthalene core slows
the rate of metal-halogen exchange even with use of an aryl
iodide, rendering most Grignard reagents ineffective. Subse-
quent efforts to overcome this problem by enlisting lithium-
halogen exchange followed by transmetalation onto either a
Grignard reagent or a cuprate did provide the desired alcohol 6.
However, the best attainable yields were still low even after
optimization (20-40%). These observations led to the ex-
amination of a range of more reactive Grignard reagents.28
Whereas such reagents including i-PrMgCl LiCl, i-Pr2Mg
3
3
LiCl, and s-Bu2Mg LiCl provided substantial amounts of
3
Results and Discussion
side products arising from alkyl or chloride addition to the
epoxide, the treatment of 5 with MeMgBr, EtMgBr, or i-
PrMgBr provided 6 directly in high yields (82-87%), pre-
cluding the need for transmetalation onto copper. Forma-
tion of the aryl Grignard by metal-halogen exchange (2.0
equiv of EtMgBr, 23 °C, 30 min) was followed by the rapid
intramolecular ring-opening to give exclusively 6, the result
of intramolecular 6-endo versus 5-exo addition to the ep-
oxide. MeMgBr and i-PrMgBr also provide 6 in high yields
(82-87%), albeit requiring larger amounts of the Grignard
reagent (10 equiv). Representative studies defining reaction
conditions and the number of equivalents of each reagent
necessary to optimize yields are summarized in Table 1.
Hydrogenolysis removal of the benzyl ether (10% Pd/C,
HCO2NH4, 9:1 THF/MeOH) provided 7, and direct trans-
annular Ar-30 spirocyclization upon Mitsunobu activation
Synthesis. Alkylation of 4, prepared in 5-steps from 1,3-
dihydroxynaphthalene,13 with recrystallized (S)-glycidal-3-
(16) Boger, D. L.; Yun, W. J. Am. Chem. Soc. 1994, 116, 7996.
(17) Boger, D. L.; Ishizaki, T.; Kitos, P. A.; Suntornwat, O. J. Org. Chem.
1990, 55, 5823.
(18) Boger, D. L.; McKie, J. A.; Boyce, C. W. Synlett 1997, 515.
(19) Kastrinsky, D. B.; Boger, D. L. J. Org. Chem. 2004, 69, 2284.
(20) (a) Ling, L.; Xie, Y.; Lown, J. W. Heterocycl. Commun. 1997, 3, 405.
(b) Lei, L.; Lown, J. W. Chem. Commun. 1996, 1559.
(21) Aristoff, P. A.; Johnson, P. D. J. Org. Chem. 1992, 57, 6234.
(22) Mohamadi, F.; Spees, M. M.; Staten, G. S.; Marder, P.; Kipka, J. K.;
Johnson, D. A.; Boger, D. L.; Zarrinmayeh, H. J. Med. Chem. 1994, 37, 232.
(23) Tse, W. C.; Boger, D. L. Chem. Biol. 2004, 11, 1607.
(24) (a) Lajiness, J. P.; Robertson, W. M.; Dunwiddie, I.; Broward, M. A.;
Vielhauer, G. A.; Weir, S. J.; Boger, D. L. J. Med. Chem. 2010, 53, 7731.
(b) Jin, W.; Trzupek, J. D.; Rayl, T. J.; Broward, M. A.; Vielhauer, G. A.;
Weir, S. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2007, 129, 15391.
(25) Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002, 102, 2477.
(26) Tichenor, M. S.; Trzupek, J. D.; Kastrinsky, D. B.; Shiga, F.;
Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 15683.
(27) Hanson, R. M. Chem. Rev. 1991, 91, 437.
(28) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 159.
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TABLE 1. Optimization of Grignard Formation and Cyclization
at -78 °C for 30 min, followed by warming to room
temperature and stirring for 30 min, resulting in regioselec-
tive cleavage of the cyclopropane and subsequent N-Boc
deprotection. Following solvent removal under a stream of
nitrogen, the residue was treated with indole2-CO2H and
EDCI in DMF and stirred for 16 h, providing seco-CBI-
indole2 (10) in good yield (68%).
Conclusions
equiv
time
result
An effective (9-step, 31% overall) asymmetric synthesis of
N-Boc-CBI was developed that provides the optically pure
(99% ee) material. The key late stage step introducing the
chirality proceeds in excellent yields (82-87%). Thus, treat-
ment of key intermediate 5 with EtMgBr, MeMgBr, or i-
PrMgBr afforded the desired secondary alcohol 6 directly in
superb chemical yield and regioselectivity. This route should
prove useful in the future preparation and evaluation of CC-
1065 and duocarmycin analogues.
EtMgBr
MeMgBr
i-PrMgBr
1.0
2.0
4.0
6.0
10.0
1.0
2.0
3.0
4.0
10.0
1.0
2.0
3.0
4.0
10.0
120 min
30 min
30 min
30 min
10 min
24 h
33%
87%
84%
80%
83%
<1%
7%
30%
38%
87%
<1%
26%
41%
67%
82%
24 h
24 h
24 h
30 min
120 min
120 min
120 min
120 min
10 min
Experimental Section
(R)-tert-Butyl (4-(Benzyloxy)-1-iodonaphthalen-2-yl)(oxiran-
2-ylmethyl)carbamate (5). A solution of 4 (750 mg, 1.58 mmol)
in anhydrous DMF (10 mL) was cooled to 0 °C and treated with
NaH (60% dispersion in mineral oil, 76.0 mg, 1.90 mmol). The
solution was stirred for 5 min before solid recrystallized (S)-
glycidal-3-nosylate (99% ee, 491 mg, 1.90 mmol) was added.
The reaction mixture was stirred at 0 °C for 30 min, after which it
was warmed to room temperature and stirred for 2 h. The
solution was quenched with the addition of saturated aqueous
NH4Cl, diluted with EtOAc, washed with H2O and saturated
aqueous NaCl, and dried (Na2SO4). The solvent was removed
under reduced pressure and the residue was purified by flash
chromatography (15% EtOAc/hexane) to provide 5 (735 mg,
SCHEME 2
1
88%) as a white solid and as a mixture of rotamers (1:1): H
NMR (acetone-d6, 400 MHz) δ 8.34-8.31 (m, 1H), 8.23-8.20
(m, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.64-7.56 (m, 3H), 7.44 (t, J =
7.2 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.23 (s, 0.5H), 7.14 (s,
0.5H), 5.40 (s, 2H), 4.12-4.02 (m, 1H), 3.39-3.25 (m, 2H),
2.69-2.62 (m, 1H), 2.41-2.35 (m, 1H), 1.30 (s, 9H); 13C NMR
(acetone-d6, 150 MHz) δ 157.13, 157.07, 155.23, 155.16, 145.8,
145.4, 138.70, 138.67, 137.04, 136.98, 134.30, 134.28, 130.50,
130.48, 130.40, 129.84, 129.82, 129.7, 129.6, 129.4, 129.3, 128.3,
128.2, 127.2, 124.22, 124.20, 109.99, 109.96, 96.1, 96.0, 81.6,
81.5, 72.1, 72.0, 54.3, 53.0, 51.3, 50.8, 47.4, 47.0, 29.34, 29.32; IR
(film) νmax 2975, 1700, 1589 cm-1; ESI-TOF HRMS m/z
532.0975 (M þ Hþ, C25H26INO4 requires 532.0979).
of the secondary alcohol (3.0 equiv of 1,10-(azodicarbonyl)-
dipiperidine (ADDP), 3.0 equiv of Bu3P, toluene, 23 °C, 1 h,
71%) provided N-Boc-CBI (8), which proved identical in all
respects to authentic material. Confirmation of the absolute
configuration was made by comparison ([R]D, HPLC Chir-
alcel OD, tR) with authentic material for which the stereo-
chemical assignment was previously established by X-ray of
a heavy atom derivative.9 The optical purity of 8 was deter-
mined by chiral phase HPLC (Chiralcel OD column, 7 mL/
min, 10% i-PrOH/hexane) and established to be 99% ee (see
Figure 3, Supporting Information).
Additionally, 8 can be converted to N-Boc-seco-CBI (9),
resulting from a stereoelectronically controlled regioselective
cyclopropane cleavage, in near quantitative yield by treat-
ment with 4 N HCl in EtOAc at -78 °C for 30 min, followed
by solvent removal under a stream of nitrogen while at -78 °C
(Scheme 2). A procedure for the direct attachment of the
DNA binding subunits onto 8 was also developed. This was
accomplished by treatment of 8 with 4 N HCl in EtOAc
5: [R]23D þ8 (c 2.0, THF). ent-5: [R]23D -8 (c 2.0, THF).
(S)-tert-Butyl 6-(Benzyloxy)-2-hydroxy-2,3-dihydrobenzo-
[f]quinoline-4(1H)-carboxylate (6). A solution of 5 (126.5 mg,
0.2381 mmol) in distilled anhydrous THF (1.3 mL) at room
temperature was treated with EtMgBr (476 μL, 0.4761 mmol,
1.0 M in THF). The reaction mixture was stirred for 30 min,
after which the reaction was quenched with the addition of satu-
rated aqueous NH4Cl, diluted with EtOAc, washed with H2O
and saturated aqueous NaCl, and dried (Na2SO4). The solvent
was removed under reduced pressure and the residue was
purified by flash chromatography (20% EtOAc/hexane) to
provide 6 as a clear oil (84.5 mg, 87%): 1H NMR (acetone-d6,
400 MHz) δ 8.26 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H),
7.60 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 8.4 Hz, 1H), 7.44 (t, J = 7.2
Hz, 3H), 7.37 (t, J = 7.2 Hz, 2H), 5.28 (s, 2H), 4.33 (d, J = 4.4
Hz, 1H), 4.28 (m, 1H), 3.99 (dd, J = 13, 3.2 Hz, 1H), 3.56 (dd,
J = 12, 8.0 Hz, 1H), 3.37 (dd, J = 13, 6.4 Hz, 1H), 2.92 (dd, J =
17, 6.0 Hz, 1H), 1.53 (s, 9H); 13C NMR (acetone-d6, 150 MHz) δ
155.7, 153.8, 139.3, 138.2, 134.8, 130.4, 129.7, 129.4, 128.7,
586 J. Org. Chem. Vol. 76, No. 2, 2011

Lajiness and Boger
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stream of nitrogen, providing 9 as a light brown solid (2.7 mg,
126.0, 125.3, 124.4, 124.0, 115.7, 106.4, 82.2, 71.8, 66.1, 51.9,
35.0, 29.5; IR (film) νmax 3414, 2975, 2928, 1692, 1622, 1592 cm-1
1
;
96%), identical in all respects to authentic material: H NMR
ESI-TOF HRMS m/z 406.2014 (M þ Hþ, C25H27NO4 requires
(acetone-d6, 400 MHz) δ 8.19 (d, J = 8.0 Hz, 1H), 7.77 (d, J =
8.4 Hz, 1H), 7.73 (br s, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.31 (t, J =
8.4 Hz, 1H), 4.20 (dd, J = 11, 2.4 Hz, 1H), 4.15 (t, J = 10 Hz,
1H), 4.07 (m, 1H), 3.99 (dd, J = 11, 3.2 Hz, 1H), 3.66 (dd, J =
11, 8.8 Hz, 1H), 1.57 (s, 9H); 13C NMR (acetone-d6, 150 MHz) δ
156.4, 153.9, 132.6, 129.2, 127.0, 125.2, 124.2, 124.0, 123.4,
115.6, 100.8, 82.5, 54.6, 48.9, 42.9, 29.6; ESI-TOF HRMS m/z
334.1218 (M þ Hþ, C18H20ClNO3 requires 334.1204).
406.2013).
6: [R]D þ35 (c 0.41, THF). ent-6: [R]D -34 (c 0.41, THF).
Treatment with MeMgBr (10 equiv) or i-PrMgBr (10 equiv)
using the above procedure provided 6 in 87 and 82%, respectively.
(S)-tert-Butyl 2,6-Dihydroxy-2,3-dihydrobenzo[f]quinoline-
4(1H)-carboxylate (7). A solution of 6 (84.7 mg, 0.209 mmol)
and ammonium formate (130 mg, 2.09 mmol) in 9:1 distilled
THF:MeOH (8 mL) at room temperature was treated with
10% Pd/C (40 mg). The reaction mixture was stirred for
30 min, at which point the solution was filtered through Celite.
The solvent was removed under reduced pressure to provide 7
as a white foam (63.9 mg, 97%), identical in all respects to
authentic material: 1H NMR (acetone-d6, 400 MHz) δ 8.85 (s,
1H), 8.20 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.50 (t,
J = 7.6 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.27 (s, 1H), 4.25 (m,
2H), 3.98 (dd, J = 9.2, 2.4 Hz, 1H), 3.51 (dd, J = 12, 7.6 Hz,
1H), 3.35 (dd, J = 16, 6.0 Hz, 1H), 2.88 (dd, J = 16, 6.0 Hz,
1H), 1.51 (s, 9H); 13C NMR (acetone-d6, 150 MHz) δ 155.6,
152.4, 138.3, 135.0, 128.4, 125.3, 124.7, 124.4, 124.2, 114.3,
108.2, 81.9, 66.3, 51.9, 35.0, 29.4; IR (film) νmax 3306, 2975,
2929, 1670, 1626, 1594 cm-1; ESI-TOF HRMS m/z 316.1540
(M þ Hþ, C18H21NO4 requires 316.1543).
(S)-N-(2-(1-(Chloromethyl)-5-hydroxy-2,3-dihydro-1H-benzo[e]-
indole-3-carbonyl)-1H-indol-5-yl)-1H-indole-2-carboxamide
(seco-CBI-indole2, 10). A sample of 8 (13.5 mg, 0.0455 mmol)
at -78 °C was treated with 4 N HCl in EtOAc (1.0 mL) and
stirred at -78 °C for 30 min. The solution was warmed to 23 °C
and stirred for 30 min, at which point the solvent and HCl gas
was removed under a stream of nitrogen. The resulting residue
was dissolved in anhydrous DMF (1.0 mL) and EDCI (26.1 mg,
0.136 mmol) and indole2-CO2H (16.0 mg, 0.0500 mmol) were
added. The resulting reaction mixture was stirred for 18 h, at
which point the solution was diluted with EtOAc, washed with 1
M HCl, saturated aqueous NaHCO3, saturated aqueous NaCl,
and dried (Na2SO4). The solvent was removed under reduced
pressure and the residue was purified by flash chromatography
(40% THF/hexane) to provide 10 as a pale yellow solid (16.5 mg,
1
7: [R]D þ42 (c 0.94, THF). ent-7: [R]D -41 (c 1.13, THF).
1 2,9,9a-Tetrahydrocyclopropa[c]benzo[e]indol-4-one (N-Boc-
CBI, 8). A solution of 7 (10.6 mg, 0.0336 mmol) in toluene
(1 mL) at room temperature was treated with ADDP (42.4 mg,
0.168 mmol) and tributyl phosphine (42 μL, 0.168 mmol). The
reaction mixture was stirred for 30 min, at which point the
solvent was removed under reduced pressure and the residue was
purified by flash chromatography (30% EtOAc/hexane) to
provide 8 (7.1 mg, 71%) as a white solid, identical in all respects
to authentic material: 1H NMR (acetone-d6, 400 MHz) δ 8.08 (d,
J = 8.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 8.0 Hz,
1H), 7.10 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 4.04 (m, 2H), 3.03 (m,
1H), 1.66 (dd, J = 7.6, 4.0 Hz, 1H), 1.54 (s, 9H), 1.49 (t, J = 4.4
Hz, 1H); 13C NMR (acetone-d6, 150 MHz) δ 186.3, 162.0, 153.3,
142.5, 134.6, 133.4, 127.9, 127.8, 123.7, 109.5, 84.0, 54.8, 34.9,
30.4, 29.2, 25.4; IR (film) νmax 2975, 2929, 1723, 1626, 1600, 1564
cm-1; ESI-TOF HRMS m/z 298.1439 (MþHþ, C18H19NO3
requires 298.1438).
68%), identical in all respects to authentic material: H NMR
(DMSO-d6, 400 MHz) δ 11.74 (s, 1H), 11.72 (s, 1H), 10.44 (s,
1H), 10.17 (s, 1H), 8.23 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.99 (s,
1H), 7.87 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.59 (dd,
J = 8.8, 1.6 Hz, 1H), 7.55-7.47 (m, 3H), 7.43 (s, 1H), 7.37 (t,
J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.07 (t,
J = 7.6 Hz, 1H), 5.28 (s, 2H), 4.83 (t, J = 10 Hz, 1H), 4.58 (d,
J = 7.2 Hz, 1H), 4.24 (m, 1H), 4.04 (dd, J = 11, 3.2 Hz, 1H), 3.89
(dd, J = 11, 7.2 Hz, 1H); 13C NMR (DMSO-d6, 125 MHz) δ
160.0, 159.5, 154.1, 142.2, 136.6, 133.3, 131.8, 131.6, 131.3,
129.8, 127.2, 127.05, 127.02, 123.4, 123.1, 123.0, 122.7, 122.1,
121.5, 119.7, 119.2, 114.9, 112.8, 112.3, 112.2, 105.6, 103.3,
100.3, 55.0, 47.6, 41.1; ESI-TOF HRMS m/z 535.1544 (M þ
Hþ, C31H23ClN4O3 requires 535.1531).
Acknowledgment. We gratefully acknowledge the finan-
cial support of the National Institutes of Health (CA 041986)
and the Skaggs Institute for Chemical Biology and thank R.
Rodriguez for initial studies. J.P.L. is a Skaggs Fellow.
8: [R]D þ131 (c 0.53, THF). ent-8: [R]D -129 (c 0.60, THF).
(S)-tert-Butyl 1-(Chloromethyl)-5-hydroxy-1H-benzo[e]indole-
3(2H)-carboxylate (N-Boc-seco-CBI, 9). A sample of 8 (2.5
mg, 0.0084 mmol) at -78 °C was treated with 4 N HCl in EtOAc
(0.5 mL) and stirred at -78 °C for 30 min. While keeping the
solution cooled, the solvent and HCl gas was removed under a
Supporting Information Available: General experimental
details, Figure 3, and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 587