Synthesis and preliminary evaluation of duocarmycin analogues incorporating the 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[2,3-e]indol-4-one (CNI) and 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[1,2-e]indol-4-one (iso-CNI) alkylation subunits

Article abstract of DOI:10.1016/j.tet.2009.02.065

Efficient syntheses and a preliminary evaluation of 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[2,3-e]-indole (CNI) and 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[1,2-e]indole (iso-CNI), and their derivatives containing an anthracene and phenanthrene variant

Full text of DOI:10.1016/j.tet.2009.02.065

Tetrahedron 65 (2009) 6591–6599
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and preliminary evaluation of duocarmycin analogues incorporating the
1,2,11,11a-tetrahydrocyclopropa[c]naphtho[2,3-e]indol-4-one (CNI) and 1,2,11,11a-
tetrahydrocyclopropa[c]naphtho[1,2-e]indol-4-one (iso-CNI) alkylation subunits
Carla M. Gauss, Akiyuki Hamasaki, Jay P. Parrish, Karen S. MacMillan, Thomas J. Rayl,
*
Inkyu Hwang, Dale L. Boger
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient syntheses and a preliminary evaluation of 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[2,3-e]-
indole (CNI) and 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[1,2-e]indole (iso-CNI), and their derivatives
containing an anthracene and phenanthrene variant of the CC-1065 or duocarmycin alkylation subunit
are detailed.
Received 17 December 2008
Received in revised form 21 February 2009
Accepted 24 February 2009
Available online 3 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
H2N
CC-1065 (1),1 the duocarmycins (2 and 3),2–4 and yatakemycin
(4)5 are the parent members of a class of potent antitumor antibi-
otics that derive their properties through a sequence-selective
alkylation of duplex DNA (Fig. 1).6,7 Extensive studies have char-
acterized their structural features responsible for the DNA alkyl-
ation reaction and have established fundamental relationships
between their structure and reactivity or activity.6–11 Aside from
the structural complexity inherent in the alkylation subunit, they
possess a stability that defies intuition. This is due to the vinylogous
amide conjugation and stabilization of the cyclohexadienone
structure, which is dominant over that activating the cross-conju-
gated cyclopropane.12–14 Accordingly, disruption of this vinylogous
amide conjugation leads to remarkable increases in reactivity as
large as 104-fold14 that we have suggested is the source of catalysis
for the DNA alkylation reaction.8–12
The synthesis of analogues containing deep-seated structural
changes has been central to these studies providing insights not
accessible through examination of the natural products them-
selves.15 The two most significant being the delineation of a fun-
damental parabolic relationship between reactivity and cytotoxic
potency16,17 and that the catalysis for the DNA alkylation reaction
likely entails a DNA binding induced conformation change that
disrupts the alkylation subunit stabilizing vinylogous amide con-
jugation.8,9,12 Among the modified alkylation subunits introduced,
the 1,2,9,9a-tetrahydrocyclopropa[c]benz[1,2-e]indol-4-one (CBI)18
alkylation subunit has emerged as the most extensively examined
O
N
OH
HN
OMe
NH
N
N
O
O
O
1, (+)-CC-1065
N
H
OH
OMe
MeO2C
MeO2C
Me
HN
O
HN
N
OMe
OMe
O
N
OMe
OMe
O
O
N
H
O
N
OMe
H
OMe
3, (+)-duocarmycin SA
2, (+)-duocarmycin A
OH
O
OMe
MeS
HN
NH
O
N
N
MeO
OH
O
N
H
O
4, yatakemycin
* Corresponding author. Tel.: þ1 858 784 7522; fax: þ1 858 784 7550.
E-mail address: boger@scripps.edu (D.L. Boger).
Figure 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.065

6592
C.M. Gauss et al. / Tetrahedron 65 (2009) 6591–6599
(EtO)2P(O)
Cl
t
Br
CO2 Bu
CO2Et
NaH, THF, 68%
Br
CO2Et
CO2R
12, R = Bu
13, R = H
CHO
N
N
O
O
O
HO
HO
HO
CBI, 5
R
R
R
R
6
t
O
O
11
Br
16
TFA, 86%
1. Ac2O, NaOAc, 61%
2. K2CO3, 100%
Cl
Br
N
N
CO2H
CO2Et
LiOH, H2O, 100%
R
CNI, 7
8
O
O
OBn
DPPA, t-BuOH, 86%
OR
14, R = H
Cl
BnBr, 77%
15, R = Bn
N
N
Br
Br Br
R
NHBoc
NHBoc
iso-CNI, 9
10
NBS, TsOH
THF, 74%
O
O
Figure 2.
OBn
OBn
17
18
Cl
Cl
series, Figure 2. Not only is it the most synthetically19 accessible
alkylation subunit in a rich series, but its derivatives exhibit bio-
NaH, DMF, 93%
logical properties18,20 that surpass those of
1 and 2 while
Br
Br
Cl
N
approaching those of 3, and it exhibits a stability and inherent
Bu3SnH, AIBN
toluene, 69%
reaction regioselectivity that are near optimal.18
Cl
As an extension of these studies, we report herein two new
classes of CBI-based agents that incorporate the extended anthra-
cene and phenanthrene skeleton. Prospective modeling of the
former linear 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[2,3-e]-
indol-4-one (CNI) suggested that its derivatives may effectively
bind DNA with its extended alkylation subunit productively en-
hancing catalysis of the DNA reaction, whereas the latter angular
1,2,11,11a-tetrahydrocyclopropa[c]naphtho[1,2-e]indol-4-one (iso-
CNI) derivatives may suffer destabilizing steric interactions pre-
cluding effective DNA alkylation.
BnO
N
Boc
BnO
Boc
20
19
1. Chiralcel OD Resolution
α = 1.17
2. H2, 10% Pd/C, 100%
Cl
DBU, CH3CN, 61%
N
N
HO
O
Boc
Boc
21
22
2. Results and discussion
2.1. Synthesis
Scheme 1.
N-Boc deprotection of 21 and subsequent coupling of the amine
hydrochloride salt with 5,6,7-trimethoxyindole-2-carboxylic acid
(TMI) provided 23 (47%), which was spirocyclized to provide 24
(CNI-TMI) using DBU (60%, Scheme 2).
The synthesis of the iso-CNI subunit began by the preparation of
26 following the modified Stobbe condensation previously
The synthesis of the CNI subunit began by condensation of
commercially available aldehyde 11 with the known phosphonate21
to provide 12, and was followed by selective removal of the tert-
butyl ester to provide the carboxylic acid 13 (Scheme 1). Friedel–
Crafts cyclization effected by treatment with Ac2O and subsequent
hydrolysis of the resulting acetate provided phenol 14 (61%, two
steps). Benzyl protection of the phenol (77%) and LiOH hydrolysis of
15 gave 16 (100%). Treatment of 16 with the Shioiri–Yamada re-
agent (DPPA) in t-BuOH and subsequent Curtius rearrangement of
the intermediate acyl azide provided the Boc-protected amine 17 in
86%. Regioselective C4 bromination of 17 (74%) and subsequent N-
alkylation of 18 with 1,3-dichloropropene afforded 19 (93%) and set
the stage for a key 5-exo-trig aryl radical–alkene cyclization22 to
provide 20. This latter cyclization was best effected in toluene
(105 ꢀC) and also served to reduce the C5 bromide that was used to
direct the Friedel–Crafts cyclization of 13 to provide the linear an-
thracene skeleton versus the otherwise preferred phenanthrene
skeleton.23 Resolution of 20 by chromatographic separation on
a semipreparative Chiralcel OD column provided both enantiomers
cleanly, which were then subjected to hydrogenolysis to provide 21
(natural S enantiomer shown). Spirocyclization of 21 was effected
by treatment with DBU in anhydrous CH3CN to give N-Boc-CNI (22)
in good yield (61%).
Cl
4 N HCl/EtOAc;
21
TMICO2H, EDCI
DMF, 47%
OMe
OMe
N
O
HO
N
H
23
OMe
OMe
DBU, CH3CN, 60%
OMe
OMe
N
O
O
N
H
24
Scheme 2.

C.M. Gauss et al. / Tetrahedron 65 (2009) 6591–6599
6593
CO2Et
CO2R
(EtO)2P(O)
t
CO2 Bu
CO2Et
NaH, THF, 63%
CHO
Cl
4 N HCl/EtOAc;
35
TMICO2H, EDCI
DMF, 57%
OMe
OMe
N
O
HO
25
26
N
H
1. TFA 2. Ac2O, NaOAc
3. K2CO3, 86% (3 steps)
36
OMe
LiOH, H2O, 96%
DBU, CH3CN, 60%
OMe
OMe
N
O
O
BnO
CO2H
RO
CO2Et
29
27, R = H
N
37
BnBr, 95%
H
28, R = Bn
OMe
DPPA, t-BuOH, 76%
Scheme 4.
NBS, TsOH
THF, 88%
Br
k, s−1
t
1/2
Compound
BnO
NHBoc
BnO
NHBoc
1.45 x 10−6
133 h
115 h
146 h
N-Boc-CBI
N-Boc-CNI
N-Boc-iso-CNI
30
31
1.68 x 10−6
1.32 x 10−6
Cl
Cl
NaH, DMF, 96%
Figure 3. Solvolysis reactivity, pH¼3.
Cl
Bu3SnH, AIBN
C6H6, 48%
the corresponding derivatives.16 Consequently, the solvolytic re-
activity of both N-Boc-CNI (22) and N-Boc-iso-CNI (35) at pH 3 (50%
buffer–MeOH, buffer¼0.1 M citric acid, 0.2 M Na2HPO4, and
deionized H2O) was established and compared to that of the pre-
ceding analogues including N-Boc-CBI (Fig. 3).18 Consistent with
expectations and intrinsic to their structures, both N-Boc-CNI
(t1/2¼115 h) and N-Boc-iso-CNI (t1/2¼146 h) exhibited the remark-
able stability of N-Boc-CBI (t1/2¼133 h) even at pH 3. Both were
approximately four-times more stable than the alkylation subunit
of CC-1065 (N-Boc-CPI, t1/2¼36 h)25 and approach the stability of
the alkylation subunit of duocarmycin SA and yatakemycin (N-Boc-
DSA, t1/2¼177 h).26,27
Br
Cl
N
BnO
N
BnO
Boc
Boc
33
32
1. H2, HCO2NH4, 90%
2. Chiralcel OD Resolution
α = 1.33
Cl
NaH, DMF, 54%
N
N
HO
O
Boc
Boc
34
35
Scheme 3.
2.3. Cytotoxic activity
The cytotoxic activity of the key CNI and iso-CNI derivatives was
established against L1210, a leukemia cell line utilized extensively
in past studies, Figure 4. Consistent with expectations based on
their relative reactivity, the cytotoxic activity of both N-Boc-CNI
(22) and CNI-TMI (24) proved nearly indistinguishable from the
corresponding CBI derivative. Notably, (þ)-CNI-TMI exhibited the
exceptionally potent activity observed with (þ)-CBI-TMI
(IC50¼30 pM), and the unnatural enantiomers were 10–100 fold
less active. In contrast, the iso-CNI derivatives were >10-fold less
active than either the CBI or CNI derivatives indicating that they
exhibit a diminished cytotoxic activity relative to expectations
based on their reactivity. Such observations are consistent with
described (Scheme 3). Selective removal of the tert-butyl ester,
Friedel–Crafts cyclization to the phenanthrene effected by treat-
ment with Ac2O, and hydrolysis of the resulting acetate provided
phenol 27 (86% over three steps). Benzyl protection of 27 (95%) and
LiOH hydrolysis of 28 gave the carboxylic acid 29 (96%), which was
subjected to a modified Curtius rearrangement for conversion to
the Boc-protected amine 30. Regioselective C4 bromination, sub-
sequent N-alkylation with 1,3-dichloropropene, and 5-exo-trig aryl
radical–alkene cyclization gave 33.24 Resolution of 33 by chro-
matographic separation on a semipreparative Chiralcel OD column
provided both enantiomers cleanly, which were subjected to
transfer hydrogenolysis to provide 34 (natural S enantiomer
shown). Spirocyclization of 34 was effected by treatment with NaH
to give N-Boc-iso-CNI (35) in good yield (54%).
Compound
Compound
Boc deprotection of 34 and subsequent coupling of the amine
hydrochloride salt with 5,6,7-trimethoxyindole-2-carboxylic acid
(TMI) provided 36 (57%), which was spirocyclized to provide 37
(iso-CNI-TMI) using DBU (60%), Scheme 4.
IC50
80
0.03
60
0.03
IC50
nat. enantiomer
unnat. enantiomer
(+)-N-Boc-CBI
(+)-CBI-TMI
(+)-N-Boc-CNI
(+)-CNI-TMI
(−)-N-Boc-CBI
(−)-CBI-TMI
(−)-N-Boc-CNI
(−)-CNI-TMI
900
2
800
0.8
2.2. Solvolysis reactivity
(+)-N-Boc-iso-CNI 500
(+)-iso-CNI-TMI
(−)-N-Boc-iso-CNI 10000
(−)-iso-CNI-TMI 20
1
A key feature of the alkylation subunits is their intrinsic re-
activity (stability), which correlates with the cytotoxic potency of
Figure 4. In vitro cytotoxic activity, L1210 (nM).

6594
C.M. Gauss et al. / Tetrahedron 65 (2009) 6591–6599
modeling studies that suggest they suffer from a less effective
interaction with the minor groove of duplex DNA.
for 20 h. The mixture was cooled and the solvent was removed
in vacuo, followed by azeotropic distillation with toluene
(3ꢁ50 mL) until the Ac2O was completely removed. Flash
chromatography (SiO2, 3.5ꢁ16 cm, 6–16% EtOAc–hexanes
gradient) afforded ethyl 4-acetoxyphenanthrene-2-carboxylate
(170 mg, 25%) as a yellow film and the title compound (400 mg,
61%) as a yellow solid. Mp 71–73 ꢀC; Rf¼0.49 (10% EtOAc–hex-
3. Conclusions
Efficient syntheses and a preliminary evaluation of 1,2,11,11a-
tetrahydrocyclopropa[c]naphtho[2,3-e]indole (CNI) and 1,2,11,11a-
tetrahydrocyclopropa[c]naphtho[1,2-e]indole (iso-CNI), and their
derivatives containing an anthracene and phenanthrene variant of
the CC-1065 or duocarmycin alkylation subunit are detailed. Both
were found to exhibit a reactivity comparable with the prototypical
CBI derivatives, but only the former CNI derivatives exhibited the
comparable cytotoxic activity. Further studies into the origin of the
distinctions are in progress and will be reported in due course.
anes); 1H NMR (400 MHz, CDCl3)
d
9.23 (s, 1H), 8.52 (d, J¼8.8 Hz,
1H), 8.43 (s, 1H), 8.00 (d, J¼8.4 Hz, 1H), 7.83 (s, 1H), 7.65 (t,
J¼7.6 Hz, 1H), 7.57 (t, J¼7.5 Hz, 1H), 4.49 (q, J¼7.1 Hz, 2H), 2.56
(s, 3H), 1.48 (t, J¼7.1 Hz, 3H), 1.45 (t, J¼6.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d 169.5, 166.1, 147.8, 134.4, 131.7, 131.0, 129.9,
129.4, 129.3, 128.2, 128.1, 127.5, 125.7, 121.4, 117.0, 104.2, 61.0,
20.7, 14.7; IR (film) nmax 2958, 1769, 1715, 1365, 1231, 1197 cmꢂ1
;
HRMALDI–FTMS (DHB) m/z 409.0058 (MþNaþ, C19H15BrO4 re-
4. Experimental section
quires 409.0046).
For ethyl 4-acetoxyphenanthrene-2-carboxylate: yellow solid.
4.1. 4-tert-Butyl 1-ethyl 2-(1-bromonaphthalen-2-yl-
1H NMR (400 MHz, CDCl3)
d 9.01 (m, 1H), 8.20 (s, 1H), 7.91 (m,
methylene)butanedioate (12)
1H), 7.75 (d, J¼7.7 Hz, 1H), 7.67 (d, J¼7.7 Hz, 1H), 7.61 (m, 4H),
4.41 (q, J¼6.4 Hz, 2H), 2.55 (s, 3H), 1.40 (t, J¼6.4 Hz, 3H); 13C NMR
A
solution of 4-tert-butyl 1-ethyl 2-(diethoxyphosphoryl)-
(100 MHz, CDCl3) d 168.4, 166.3, 134.7, 133.0, 131.4, 129.9, 129.6,
succinate21 (8.61 g, 25.4 mmol,1.1 equiv) in THF (75 mL) was cooled
to 0 ꢀC and NaH (60% oil dispersion, 1.02 mg, 25.4 mmol, 1.1 equiv)
was added in a single addition. The reaction mixture was gradually
warmed to room temperature over 1 h. The mixture was cooled to
129.5, 129.4, 127.3, 127.2, 127.1, 126.5, 115.8, 62.1, 22.0, 4.7; IR
(film) nmax 1776, 1731, 1558, 1367, 1218, 1181, 1036 cmꢂ1
;
HRMALDI–FTMS (DHB) m/z 331.0947 (MþNaþ, C19H16O4 requires
331.0941).
0 ꢀC and
a solution of 1-bromonaphthalene-2-carbaldehyde
(5.43 g, 23.1 mmol) in THF (40 mL) was added and the mixture was
warmed to room temperature and stirred for 16 h. The mixture was
quenched with the addition of water (100 mL) and diluted with
EtOAc (100 mL). The organic layer was washed with water
(100 mL), saturated aqueous NaCl (100 mL), dried (Na2SO4), and
concentrated in vacuo. Flash chromatography (SiO2, 4ꢁ12 cm, 0–
10% EtOAc–hexanes) afforded 12 (6.62 g, 68%) as a yellow viscous
4.4. Ethyl 9-bromo-4-hydroxyanthracene-2-carboxylate (14)
A solution of ethyl 4-acetoxy-9-bromoanthracene-2-carboxyl-
ate (2.00 g, 5.18 mmol) in EtOH (52 mL) was treated with K2CO3
(787 mg, 5.70 mmol, 1.1 equiv) and the reaction mixture was
stirred for 4 h at 23 ꢀC. The mixture was diluted with EtOAc
(50 mL), washed with saturated aqueous NH4Cl (100 mL), dried
(Na2SO4), and concentrated in vacuo. Flash chromatography (SiO2,
4ꢁ30 cm, 0–10% EtOAc–hexanes gradient) afforded 14 (1.78 g,
100%) as a yellow solid. Mp 197–199 ꢀC; Rf¼0.28 (16% EtOAc–
oil. Rf¼0.49 (10% EtOAc–hexanes); 1H NMR (400 MHz, CDCl3)
d 8.34
(d, J¼8.9 Hz, 1H), 8.05 (s, 1H), 7.85–7.81 (m, 2H), 7.62 (dt, J¼1.4,
7.6 Hz,1H), 7.56 (dt, J¼1.4, 7.5 Hz,1H), 7.40 (d, J¼8.4 Hz,1H), 4.33 (q,
J¼6.1 Hz, 2H), 3.32 (s, 2H), 1.46 (s, 9H), 1.38 (t, J¼7.1 Hz, 3H); 13C
hexanes); 1H NMR (500 MHz, CDCl3)
d 8.95 (s, 1H), 8.88 (s, 1H),
NMR (100 MHz, CDCl3)
d 170.0, 167.0, 141.5, 134.0, 133.8, 132.2,
8.54 (d, J¼8.5 Hz, 1H), 8.07 (d, J¼8.5 Hz, 1H), 7.65 (t, J¼7.7 Hz, 1H),
128.5, 128.1, 127.8, 127.7, 127.20, 127.18, 126.5, 124.4, 81.0, 61.2, 35.1,
7.58 (t, J¼7.7 Hz, 1H), 7.41 (s, 1H), 5.76 (br s, 1H), 4.49 (q, J¼7.0 Hz,
28.0 (3C), 14.2; IR (film) nmax 2977, 2948, 1725, 1720, 1367, 1256,
2H), 1.48 (t, J¼7.0 Hz, 3H); 1H NMR (400 MHz, DMSO-d6)
d 11.09
1152 cmꢂ1
C21H23BrO4 requires 441.0672).
;
HRMALDI–FTMS (DHB) m/z 441.0679 (MþNaþ,
(s, 1H), 8.93 (s, 1H), 8.57 (s, 1H), 8.36 (dd, J¼0.8, 8.8 Hz, 1H), 8.23
(d, J¼8.5 Hz, 1H), 7.72 (dt, J¼1.2, 7.7 Hz, 1H), 7.61 (dt, J¼1.5, 7.5 Hz,
1H), 7.35 (d, J¼1.3 Hz, 1H), 4.39 (q, J¼7.1 Hz, 2H), 1.38 (t, J¼7.1 Hz,
4.2. (E)-3-(Ethoxycarbonyl)-4-(1-bromonaphthalen-2-yl)-
but-3-enoic acid (13)
3H); IR (film) nmax 3409, 2953, 1697, 1595, 1243, 1107, 1031 cmꢂ1
;
HRMALDI–FTMS (DHB) m/z 344.0045 (Mþ, C17H13BrO3 requires
344.0048).
A solution of 12 (1.62 g, 3.87 mmol) in TFA (18 mL) was cooled to
0 ꢀC and H2O (2 mL) was added. The reaction mixture was gradually
warmed to room temperature over 2 h before the solvent was re-
moved in vacuo, followed by azeotropic distillation with toluene
(3ꢁ50 mL) until the TFA was completely removed. Flash chroma-
tography (SiO2, 2.5ꢁ25 cm, 50–99% EtOAc–hexanes gradient)
afforded 13 (1.20 g, 86%) as a white solid. Mp 171–173 ꢀC (dec);
4.5. Ethyl 4-benzyloxy-9-bromoanthracene-2-carboxylate (15)
A solution of 14 (800 mg, 2.33 mmol) in DMF (23 mL) was
treated with K2CO3 (354 mg, 2.56 mmol, 1.1 equiv) and after 5 min,
BnBr (0.31 mL, 2.56 mmol, 1.1 equiv) was added. The mixture was
stirred for 3.5 h at 23 ꢀC, then diluted with EtOAc (50 mL) and
washed with saturated aqueous NH4Cl (100 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo. Flash chromato-
graphy (SiO2, 4ꢁ30 cm, 0–10% EtOAc–hexanes gradient) afforded
15 (777 mg, 1.78 mmol, 77%) as a yellow solid. Mp 124–126 ꢀC;
Rf¼0.30 (10% EtOAc–hexanes); 1H NMR (500 MHz, CDCl3)
d 8.34 (d,
J¼8.4 Hz, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.85 (s, 1H), 7.64 (dt, J¼1.2,
7.6 Hz,1H), 7.58 (dt, J¼1.0, 7.5 Hz, 1H), 7.41 (d, J¼8.4 Hz, 1H), 4.36 (q,
J¼7.1 Hz, 2H), 3.46 (s, 2H), 1.39 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d 176.9, 166.9, 142.7, 134.1, 133.3, 132.1, 128.2, 128.0, 127.9,
127.4, 127.2, 127.1, 126.3, 124.4, 61.5, 33.8, 14.2; IR (film) nmax 3226,
2950, 2919, 2847, 1707, 1461 cmꢂ1; HRMALDI–FTMS (DHB) m/z
385.0049 (MþNaþ, C17H15BrO4 requires 385.0046).
Rf¼0.50 (16% EtOAc–hexanes); 1H NMR (500 MHz, CDCl3)
d 8.87 (s,
1H), 8.84 (s, 1H), 8.47 (d, J¼8.8 Hz, 1H), 7.98 (d, J¼8.1 Hz, 1H), 7.62–
7.58 (m, 3H), 7.53–7.40 (m, 5H), 5.34 (s, 2H), 4.50 (q, J¼7.0 Hz, 2H),
1.52 (t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 167.1, 155.0,
4.3. Ethyl 4-acetoxy-9-bromoanthracene-2-carboxylate
137.0, 133.2, 131.6, 130.4, 129.2, 129.1, 128.7, 128.2, 127.80, 127.77,
127.72, 126.9, 126.4, 124.4, 123.9, 122.3, 102.2, 71.0, 61.8, 14.9; IR
(film) nmax 1717, 1653, 1558 cmꢂ1; HRMALDI–FTMS (DHB) m/z
434.0529 (Mþ, C24H19BrO3 requires 434.0512).
A solution of 13 (800 mg, 2.21 mmol) in Ac2O (45 mL) was
treated with NaOAc (480 mg, 11.05 mmol) and warmed at 110 ꢀC

C.M. Gauss et al. / Tetrahedron 65 (2009) 6591–6599
6595
4.6. 4-Benzyloxy-9-bromoanthracene-2-carboxylic acid (16)
For 2-(tert-butyloxycarbonyl)amino-4-hydroxy-1,9-dibromoan-
thracene. Orange solid; Rf¼0.30 (10% EtOAc–hexanes); 1H NMR
A solution of 15 (220 mg, 0.507 mmol) in 3:1:1 (v/v/v) THF–
MeOH–H2O (5 mL) was treated with LiOH (59 mg, 1.39 mmol,
5 equiv) and stirred for 2 h at 23 ꢀC. HCl (4 N, 10 mL) was added and
the mixture was diluted with CH2Cl2 (25 mL). The organic layer was
washed with H2O (3ꢁ10 mL), dried (Na2SO4), and concentrated in
vacuo. Flash chromatography (SiO2, 1.5ꢁ12.7 cm, 50–100% EtOAc–
hexanes gradient) afforded 16 (204 mg, 100%) as a yellow solid. Mp
291–293 ꢀC (dec); Rf¼0.32 (50% EtOAc–hexanes); 1H NMR
(500 MHz, CDCl3)
d
8.85 (s, 1H), 8.66 (d, J¼8.5 Hz, 1H), 8.07 (d,
J¼7.7 Hz, 1H), 7.82 (t, J¼7.0 Hz, 1H), 7.72 (t, J¼7.0 Hz, 1H), 7.09 (s,
1H), 1.58 (s, 9H); IR (film) nmax 3374, 2985, 2912, 1743, 1666, 1605,
1462, 1253, 1149 cmꢂ1
.
4.9. 2-[N-(tert-Butyloxycarbonyl)-N-(3-chloroprop-2-en-1-yl)-
amino]-4-benzyloxy-1,9-dibromoanthracene (19)
(500 MHz, DMSO-d6)
d
13.40 (brs, 1H), 8.89 (s, 1H), 8.82 (s, 1H), 8.46
A solution of 18 (1.65 g, 2.96 mmol) in DMF (50 mL) was treated
with Bu4NI (55 mg, 0.148 mmol) under Ar. The mixture was cooled
to 0 ꢀC and NaH (60% suspension in mineral oil, 296 mg, 7.40 mmol,
2.5 equiv) was added. The solution was stirred for 0.5 h and 1,3-
(d, J¼8.8 Hz,1H), 8.32 (d, J¼8.5 Hz, 1H), 7.80–7.76 (m, 1H), 7.68–7.64
(m, 3H), 7.50 (m, 3H), 7.42–7.38 (m, 1H), 5.40 (s, 2H); 13C NMR
(100 MHz, CDCl3)
d 168.6, 155.6, 137.9, 133.7, 131.8, 131.4, 131.3,
131.0, 130.0, 129.4, 129.2, 129.0 (2C), 128.3, 128.2 (2C), 127.4, 124.6,
dichloropropene (820 mL, 8.88 mmol, 3 equiv) was added. The vial
123.8, 123.1, 103.7, 71.4; IR (film) nmax 3410, 2921, 2850, 1685, 1558,
was protected from light and allowed to stir at 0 ꢀC for 2 h before
being treated with saturated aqueous NaHCO3 (5 mL). The mixture
was extracted with Et2O (3ꢁ25 mL), and the combined organic
layers were washed with H2O (3ꢁ20 mL), dried (Na2SO4), and
concentrated in vacuo. Flash chromatography (SiO2, 3ꢁ20 cm, 16%
EtOAc–hexanes) afforded 19 (1.74 g, 2.75 mmol, 93%) as a yellow
solid as a mixture of E- and Z-olefin isomers. Mp 67–69 ꢀC; Rf¼0.35
1435, 1324 cmꢂ1
;
HRMALDI–FTMS (DHB) m/z 406.0212 (Mþ,
C22H15BrO3 requires 406.0205).
4.7. 4-Benzyloxy-2-(tert-butyloxycarbonyl)amino-9-
bromoanthracene (17)
(10% EtOAc–hexanes); 1H NMR (500 MHz, acetone-d6)
d 9.07 (d,
A solution of 16 (50 mg, 0.123 mmol) in distilled t-BuOH
J¼4.4 Hz, 1H), 8.63 (d, J¼8.8 Hz, 1H), 8.12 (m, 1H), 7.71 (t, J¼7.7 Hz,
1H), 7.64 (m, 2H), 7.58 (t, J¼7.0 Hz, 1H), 7.47 (m, 2H), 7.40 (app t,
J¼7.4 Hz,1H), 7.04 (d, J¼16.0 Hz,1H), 6.23 (m, 1H), 6.15 (m, 1H), 5.47
(m, 2H), 4.67 and 4.63 (two d, J¼6.3, 5.8 Hz, 1H), 4.38–4.48 (m, 1H),
4.14 (m, 1H), 1.36 (s, 9H); IR (film) nmax 2923, 2851, 1697, 1610, 1462,
1369, 1262, 1153 cmꢂ1; HRMALDI–FTMS (DHB) m/z 552.0801
(MþꢂBr, C29H27BrClNO3 requires 552.0801).
(1.23 mL) was treated with distilled Et3N (18.0
mL, 0.129 mmol) and
DPPA (26.5 L, 0.123 mmol, 1 equiv). The mixture was heated at
m
80 ꢀC for 20 h then cooled to room temperature and diluted with
EtOAc (1 mL). The solution was washed with saturated aqueous
NaHCO3 (2ꢁ10 mL), H2O (10 mL), and saturated aqueous NaCl
(10 mL). The organic layer was dried (Na2SO4) and concentrated in
vacuo. Flash chromatography (SiO2, 1ꢁ11 cm, 17% EtOAc–hexanes)
afforded 17 (50.4 mg, 0.105 mmol, 86%) as an orange solid. Mp 110–
112 ꢀC; Rf¼0.36 (16% EtOAc–hexanes); 1H NMR (500 MHz, CDCl3)
4.10. 5-(Benzyloxy)-3-(tert-butyloxycarbonyl)-1-(chloro-
methyl)-1,2-dihydronaphtho[2,3-e]indole (20)
d
8.83 (s, 1H), 8.43 (d, J¼8.4 Hz, 1H), 7.98 (d, J¼8.4 Hz, 1H), 7.88 (s,
1H), 7.59 (m, 3H), 7.41 (m, 4H), 7.33 (br s, 1H), 6.85 (s, 1H), 5.32 (s,
2H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3)
155.4, 152.7, 137.6,
A solution of 19 (78 mg, 0.123 mmol) in toluene (3 mL) was
d
degassed with Ar and treated with AIBN (4 mg, 24.6
mmol,
136.5,131.6,131.4,130.6, 129.3, 128.7,128.2,127.8,127.6, 127.0, 124.7,
123.0, 121.9, 120.2, 105.3, 98.3, 80.9, 71.5, 28.4 (3C); IR (film) nmax
3323, 2974, 2923, 1697, 1635, 1425, 1235, 1154 cmꢂ1; HRMALDI–
FTMS (DHB) m/z 500.0834 (MþNaþ, C26H24BrNO3 requires
500.0832).
0.2 equiv) and Bu3SnH (83 L, 0.308 mmol, 2.5 equiv). A stream of
m
Ar was bubbled through the solution for 10 min before the reaction
vessel was closed and warmed at 105 ꢀC for 3 h. The mixture was
cooled to 23 ꢀC and concentrated in vacuo. Flash chromatography
(SiO2, 1ꢁ15 cm, 67% benzene–hexanes) afforded 20 (40 mg,
0.084 mmol, 69%) as a yellow solid. Mp 152–154 ꢀC; Rf¼0.31 (16%
4.8. 4-Benzyloxy-2-(tert-butyloxycarbonyl)amino-1,9-
EtOAc–hexanes); 1H NMR (500 MHz, CDCl3)
d 8.87 (s, 1H), 8.12 (s,
dibromoanthracene (18)
1H), 8.00 (d, J¼8.1 Hz, 1H), 7.95 (d, J¼8.4 Hz, 1H), 7.61 (br m, 2H),
7.48 (m, 4H), 7.42 (m, 2H), 5.35 (s, 2H), 4.32 (br m, 1H), 4.20 (app t,
J¼9.9 Hz, 1H), 4.09 (m, 2H), 3.52 (app t, J¼10.5 Hz, 1H), 1.63 (s, 9H);
IR (film) nmax 2964, 2920, 1699, 1621, 1571, 1454, 1404, 1363, 1337,
A solution of 17 (25 mg, 0.052 mmol) in anhydrous THF (120 mL) at
ꢂ78 ꢀC was treated with anhydrous TsOH (1.0 mg, 0.0052 mmol,
0.1 equiv, dried at 50 ꢀC under high vacuum overnight) inTHF (20
mL).
1143 cmꢂ1
;
HRMALDI–FTMS (DHB) m/z 496.1631 (MþNaþ,
The solution was stirred for 5 min before NBS (9.3 mg, 0.052 mmol,
dried over P2O5 overnight) was added. The vial was protected from
light and allowed to stir at ꢂ78 ꢀC for 3 h. The reaction mixture was
warmed to 23 ꢀC and diluted with saturated aqueous NaHCO3 (1 mL).
The mixture was diluted with EtOAc (25 mL) and washed with sat-
urated aqueous NaHCO3 (10 mL), H2O (10 mL), and saturated aqueous
NaCl (10 mL). The organic layer was dried (Na2SO4) and concentrated
in vacuo. Flash chromatography (SiO2,1ꢁ11 cm, 0–7% EtOAc–hexanes
gradient) afforded 2-(tert-butyloxycarbonyl)amino-4-hydroxy-1,9-
dibromoanthracene (6.2 mg, 26%) as a tan solid and 18 (21.4 mg, 74%)
as a yellow solid. Rf¼0.34 (10% EtOAc–hexanes); 1H NMR (400 MHz,
C29H28ClNO3 requires 496.1650).
4.11. Resolution of 20
The enantiomers of 20 were resolved on a HPLC semipreparative
Diacel Chiralcel OD column (10
hexane eluant (8 mL/min). The enantiomers eluted with retention
times of 12.3 min (unnatural enantiomer) and 14.4 min (natural
m
m, 2ꢁ25 cm) using 5% i-PrOH–
enantiomer,
a¼1.17).
4.12. 3-(tert-Butyloxycarbonyl)-1-(chloromethyl)-5-hydroxy-
1,2-dihydro-3H-naphtho[2,3-e]indole (21, seco-N-Boc-CNI)
CDCl3)
J¼8.4 Hz, 1H), 7.82 (s, 1H), 7.63–7.59 (m, 3H), 7.50–7.40 (m, 4H), 5.33
(s, 2H), 1.60 (s, 9H); 13C NMR (125 MHz, CDCl3)
154.4, 152.6, 138.4,
d
8.89 (s, 1H), 8.63 (d, J¼8.9 Hz, 1H), 8.08 (s, 1H), 7.95 (d,
d
A solution of 20 (89 mg, 0.188 mmol) in THF (2 mL) was treated
with a catalytic amount of 10% Pd–C (2 mg) and placed under 1 atm
of H2. The mixture was stirred at 23 ꢀC for 1.5 h, filtered through
a Celite plug, and concentrated in vacuo. Flash chromatography
(SiO2,1ꢁ10 cm, 0–25% EtOAc/hexanes gradient) afforded 21 (72 mg,
136.2, 133.8, 130.6, 128.9, 128.7, 128.6, 128.3, 128.2, 128.1, 128.0, 125.6,
124.8, 122.5, 118.7, 98.4, 96.3, 81.4, 70.8, 28.3; IR (film) nmax 2923,
2841, 1728, 1615, 1548, 1467, 1348, 1231, 1149 cmꢂ1; HRMALDI–FTMS
(DHB) m/z 577.9929 (MþNaþ, C26H23Br2NO3 requires 577.9937).

6596
C.M. Gauss et al. / Tetrahedron 65 (2009) 6591–6599
23
23
100%) as a white solid. Mp 187–188 ꢀC (dec); Rf¼0.17 (16% EtOAc–
Compound (þ)-24: [
a]
þ160 (c 0.1, CHCl3); (ꢂ)-24: [
a]
ꢂ160 (c
D
D
hexanes); 1H NMR (500 MHz, CDCl3)
d
9.65 (d, J¼7.7 Hz, 1H), 7.92
0.1, CHCl3).
(brs, 1H), 7.84 (d, J¼7.4 Hz, 1H), 7.75 (d, J¼8.8 Hz, 1H), 7.62 (t,
J¼7.4 Hz, 1H), 7.57 (d, J¼8.8 Hz, 1H), 7.53 (t, J¼7.7 Hz, 1H), 4.29 (m,
1H), 4.14 (app t, J¼8.8 Hz, 1H), 4.00 (m, 1H), 3.92 (app d, J¼11 Hz,
1H), 3.45 (app t, J¼11 Hz, 1H), 1.66 (s, 9H); 13C NMR (125 MHz, ac-
4.16. 4-tert-Butyl 1-ethyl 2-(naphthalen-8-yl-methylene)-
butanedioate (26)
etone-d6)
d
157.4, 131.7, 130.8, 129.9, 128.8, 128.4, 127.4, 125.7, 121.7,
A solution of 4-tert-butyl 1-ethyl 2-(diethoxyphosphor-
117.1, 115.6, 105.2, 102.4, 65.0, 53.4, 47.1, 28.9 (3C), 25.7; IR
(film) nmax 3367, 2960, 2919, 1674, 1501, 1460, 1415, 1405, 1369,
1338, 1262, 1134 cmꢂ1; HRMALDI–FTMS (DHB) m/z 383.1283 (Mþ,
C22H22ClNO3 requires 383.1283).
yl)succinate21 (1.00 g, 3.0 mmol) in THF (10 mL) was cooled to 0 ꢀC
and NaH (60% oil dispersion, 79 mg, 3.3 mmol) was added in
a single addition. The reaction mixture was gradually warmed to
room temperature over 2 h before being recooled to 0 ꢀC. A solution
of 1-naphthaldehyde (462 mg, 3.0 mmol) in THF (5 mL) was added
and the mixture was warmed to room temperature and stirred for
12 h. The mixture was diluted with EtOAc (100 mL), and washed
with saturated aqueous NaHCO3 (100 mL), dried (Na2SO4), and
concentrated in vacuo. Flash chromatography (SiO2, 2.5ꢁ25 cm,
0–5% EtOAc–hexanes gradient) afforded 26 (480 mg, 63%; typically
4.13. 3-(tert-Butyloxycarbonyl)-1,2,11,11a-tetrahydrocyclo-
propa[c]naphtho[2,3-e]indol-4-one (22, N-Boc-CNI)
A sample of 21 (7.1 mg, 18.5
distilled CH3CN (200 L) under Ar. Anhydrous DBU (14
92.5
mol) was added at 23 ꢀC, and the mixture was stirred for 1 h.
mmol) was dissolved in freshly
m
mL,
m
45–66%) as a yellow oil. 1H NMR (250 MHz, CDCl3)
d 8.35 (s, 1H),
The reaction mixture was then concentrated under a stream of N2
and applied directly to PTLC (SiO2, 10ꢁ20 cm, 50% EtOAc/hexanes)
to afford 22 (3.9 mg, 61%) as a white solid. Mp 61–63 ꢀC; Rf¼0.35
7.97–7.86 (m, 3H), 7.58–7.41 (m, 4H), 4.37 (q, J¼6.9 Hz, 2H), 3.35 (s,
2H), 1.46 (s, 9H), 1.41 (t, J¼6.9 Hz, 3H); HRMALDI–FTMS (DHB) m/z
363.1564 (MþNaþ, C21H24O4 requires 363.1572).
(50% EtOAc–hexanes); 1H NMR (400 MHz, CDCl3)
d 8.77 (s, 1H), 8.01
(d, J¼8.1 Hz, 1H), 7.78 (d, J¼8.0 Hz, 1H), 7.55 (dt, J¼1.4, 7.5 Hz, 1H),
7.48 (dt, J¼1.3, 7.5 Hz, 1H), 7.28 (s, 1H), 6.88 (br s, 1H), 4.05–4.04 (m,
2H), 2.90–2.85 (m, 1H), 1.64 (dd, J¼4.3, 7.7 Hz, 1H), 1.58 (s, 9H), 1.52
4.17. Ethyl 1-hydroxyphenanthrene-3-carboxylate (27)
A solution of 26 (220 mg, 0.65 mmol) in TFA (3 mL) was cooled
to 0 ꢀC and H2O (0.1 mL) was added. The reaction mixture was
gradually warmed to room temperature over 2 h and the solvent
was removed in vacuo, followed by azeotropic distillation with
toluene (3ꢁ50 mL) until the TFA was completely removed. Ac2O
(3.5 mL) and NaOAc (53 mg, 0.65 mmol) were added and the mix-
ture was warmed at 70 ꢀC for 8 h. The mixture was cooled and the
solvent was removed in vacuo, followed by azeotropic distillation
with toluene (3ꢁ50 mL) until the Ac2O was completely removed.
The mixture was dissolved in EtOH (2.2 mL) and treated with K2CO3
(100 mg, 0.72 mmol) and the reaction mixture was stirred for 4 h at
23 ꢀC. The mixture was diluted with EtOAc (50 mL), washed with
saturated aqueous NH4Cl (100 mL), dried (Na2SO4), and concen-
trated in vacuo. Flash chromatography (SiO2, 2.5ꢁ25 cm, 5–20%
EtOAc–hexanes gradient) afforded 27 (149 mg, 86%) as an off-white
(t, J¼4.6 Hz, 1H); 13C NMR (100 MHz, acetone-d6)
d 186.4, 162.4,
153.3, 138.7, 136.7,133.4,132.8, 131.3, 129.8, 129.1, 128.6, 127.8, 122.1,
109.5, 84.1, 54.9, 31.6, 29.2 (2C), 25.4; IR (film) nmax 2977, 1723, 1614,
1382, 1256, 1160, 1140, 856, 748 cmꢂ1; HRMALDI–FTMS (DHB) m/z
348.1600 (MþHþ, C22H21NO3 requires 348.1594). Compound
23
23
(þ)-22: [
a
]
þ80 (c 0.075, CHCl3); (ꢂ)-22: [
a]
ꢂ87 (c 0.11, CHCl3).
D
D
4.14. seco-CNI-TMI (23)
A sample of 21 (11.1 mg, 28.9 mmol) was treated with 4 N HCl/
EtOAc (250
under a stream of N2 and dried under high vacuum for 30 min. The
gray residue was dissolved in DMF (20 L) and treated with 5,6,7-
trimethoxyindole-2-carboxylic acid28 (8.0 mg, 31.8
mol) and EDCI
(16.7 mg, 86.8
mol). The mixture was stirred under Ar at 23 ꢀC for
m
L) and stirred at 23 ꢀC for 1 h. The solvent was removed
m
m
m
solid. 1H NMR (250 MHz, CDCl3)
d
9.00 (s, 1H), 8.73 (d, J¼7.7 Hz,1H),
18 h in the absence of light before the solvent was removed under
a stream of N2. PTLC (SiO2, 20ꢁ20 cm, EtOAc) afforded 23 (7.1 mg,
47%) as a white solid. Mp 243–245 ꢀC (dec); Rf¼0.55 (50% EtOAc–
8.22 (d, J¼9.1 Hz, 1H), 7.93–7.81 (m, 3H), 7.72–7.60 (m, 2H), 6.79 (br
s, 1H), 4.51 (q, J¼6.9 Hz, 2H), 1.49 (t, J¼6.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3)
d 167.3, 152.4, 132.3, 131.2, 130.4, 128.7, 128.5,
hexanes); 1H NMR (500 MHz, acetone-d6)
d
10.38 (s, 1H), 8.29 (s,
128.0, 127.1, 125.1, 123.3, 120.0, 117.6, 110.2, 61.5, 14.4; IR (film) nmax
1H), 7.93 (d, J¼7.7 Hz,1H), 7.86 (m, 2H), 7.64 (t, J¼7.0 Hz,1H), 7.56 (t,
J¼7.0 Hz,1H), 7.18 (s,1H), 7.01 (s,1H), 4.81 (m,1H), 4.35 (m,1H), 4.09
(m, 2H), 4.05 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.80 (dd, J¼8.8, 2.2 Hz,
1H); IR (film) nmax 3426, 2903, 1723, 1313 cmꢂ1; HRMALDI–FTMS
(DHB) m/z 517.1511 (MþHþ, C29H25ClN2O5 requires 517.1525).
3370, 2925, 1682, 1434, 1372, 1273, 1250, 1025, 825, 749 cmꢂ1
;
HRMALDI–FTMS (DHB) m/z 266.0955 (Mþ, C17H14O3 requires
266.0943).
4.18. Ethyl 1-benzyloxyphenanthrene-3-carboxylate (28)
4.15. CNI-TMI (24)
A solution of 27 (400 mg, 1.5 mmol) in DMF (5 mL) was treated
with K2CO3 (290 mg, 2.1 mmol) and Bu4NI (12 mg, 0.03 mmol) and
A sample of 21 (7.1 mg, 13.7
distilled CH3CN (140 L) under Ar. Anhydrous DBU (10.5
68.7
mol) was added at 23 ꢀC, and the mixture was stirred for 1 h.
m
mol) was dissolved in freshly
after 5 min, BnBr (214 mL, 1.8 mmol) was added. The mixture was
m
mL,
stirred for 10 h at 23 ꢀC, then diluted with EtOAc (50 mL) and
washed with saturated aqueous NH4Cl (100 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo. Flash chromato-
graphy (SiO2, 4ꢁ30 cm, 2–20% EtOAc–hexanes gradient) afforded
28 (507 mg, 95%) as an off-white solid. 1H NMR (250 MHz, CDCl3)
m
The reaction mixture was then concentrated under a stream of N2
and applied directly to PTLC (SiO2, 10ꢁ20 cm, 50% EtOAc–hexanes)
to afford 24 (4.0 mg, 60%) as a white solid. Rf¼0.55 (50% EtOAc–
hexanes); 1H NMR (500 MHz, acetone-d6)
d
10.48 (br s, 1H), 9.99 (s,
d
9.08 (s, 1H), 8.78 (d, J¼8.4 Hz, 1H), 8.31 (d, J¼9.1 Hz, 1H), 7.93 (d,
1H), 8.10 (d, J¼8.5 Hz, 1H), 7.95 (d, J¼6.6 Hz, 1H), 7.66 (app t,
J¼7.0 Hz, 1H), 7.56 (t, J¼7.0 Hz, 1H), 7.26 (d, J¼8.5 Hz, 1H), 7.16
(s, 1H), 7.11 (s, 1H), 6.96 (s, 1H), 4.68 (dd, J¼9.9, 5.5 Hz, 1H), 4.59
(d, J¼9.9 Hz, 1H), 4.02 (s, 3H), 3.87 (s, 6H), 3.33 (m, 1H), 1.97
(d, J¼4.4 Hz, 1H), 1.79 (t, J¼5.1 Hz, 1H); IR (film) nmax 3297, 2919,
2854, 1650, 1601, 1385, 1261, 1229, 1105, 1045 cmꢂ1; HRMALDI–
FTMS (DHB) m/z 481.1751 (MþHþ, C29H24N2O5 requires 481.1758).
J¼7.7 Hz, 1H), 7.85 (d, J¼9.1 Hz, 1H), 7.73–7.58 (m, 5H), 7.49–7.38
(m, 3H), 5.35 (s, 2H), 4.50 (q, J¼7.3 Hz, 2H),1.50 (t, J¼7.3 Hz, 3H); 13C
NMR (125 MHz, CDCl3)
d 166.9, 154.9, 136.7, 132.2, 130.8, 130.3,
128.6, 128.5, 128.2, 128.0, 127.6, 127.0, 126.9, 126.2, 120.2, 117.9,
106.6, 70.5, 61.2, 14.4; IR (film) nmax 2894, 1713, 1272, 1026,
749 cmꢂ1; HRMALDI–FTMS (DHB) m/z 357.1498 (MþHþ, C24H20O3
requires 357.1491).

C.M. Gauss et al. / Tetrahedron 65 (2009) 6591–6599
6597
4.19. 1-Benzyloxyphenanthrene-3-carboxylic acid (29)
4.22. 3-[N-(tert-Butyloxycarbonyl)-N-(3-chloroprop-2-en-1-
yl)amino]-1-(benzyloxy)-4-bromophenanthrene (32)
A solution of 28 (299 mg, 0.84 mmol) in 3:1:1 (v/v/v) THF–
MeOH–H2O (7.5 mL) was treated with LiOH (60 mg, 2.5 mmol) and
stirred for 36 h at 23 ꢀC. HCl (4 N, 10 mL) was added and the mix-
ture was diluted with CH2Cl2 (25 mL). The organic layer was
washed with H2O (3ꢁ10 mL), dried (Na2SO4), and concentrated in
vacuo. Flash chromatography (SiO2, 1.5ꢁ12.7 cm, 50–100% EtOAc–
hexanes gradient) afforded 29 (264 mg, 96%) as an off-white solid.
A solution of 31 (50 mg, 0.10 mmol) in DMF (0.8 mL) was cooled
to 0 ꢀC. NaH (60% suspension in mineral oil, 12 mg, 0.30 mmol) was
added and the solution was stirred for 0.25 h. The mixture was
warmed to room temperature and 1,3-dichloropropene (28 mL,
0.3 mmol) was added. The vial was protected from light and
allowed to stir for 2 h before being treated with saturated aqueous
NaHCO3 (5 mL). The mixture was extracted with Et2O (3ꢁ25 mL),
and the combined organic layers were washed with H2O
(3ꢁ20 mL), dried (Na2SO4), and concentrated in vacuo. Flash
chromatography (SiO2, 3ꢁ20 cm, 16% EtOAc–hexanes) afforded 32
(63 mg, 96%) as a yellow oil and as a mixture of E- and Z-olefin
Mp 266–269 ꢀC (dec); 1H NMR (250 MHz, DMSO-d6)
d 8.99 (s, 1H),
8.82 (d, J¼6.6 Hz, 1H), 8.21 (d, J¼9.1 Hz, 1H), 8.06–8.02 (m, 1H), 7.99
(d, J¼9.1 Hz, 1H), 7.72 (app t, J¼9.1 Hz, 4H), 7.60 (d, J¼6.6 Hz, 2H),
7.47–7.36 (m, 2H), 5.41 (s, 2H); 13C NMR (125 MHz, DMSO-d6)
d
167.5, 154.4, 136.8, 131.8, 130.2, 129.6, 129.1, 128.7, 128.6, 128.5,
127.9, 127.5, 127.4, 125.3, 123.2, 119.6, 117.1, 107.0, 69.9; ESI (nega-
tive) m/z 327 (MꢂH, C22H15O3).
isomers. 1H NMR (250 MHz, CDCl3)
d
9.93 (d, J¼6.6 Hz, 1H),
8.32 (d, J¼9.1 Hz, 1H), 7.91–7.89 (m, 1H), 7.78 (d, J¼9.1 Hz, 1H), 7.64
(d, J¼6.2 Hz, 2H), 7.56–7.52 (m, 2H), 7.48–7.35 (m, 4H), 7.00
(d, J¼8.0 Hz, 1H), 6.92 (d, J¼13.2 Hz, 1H), 6.17–5.97 (m, 1H), 5.29
(app t, J¼6.2 Hz, 2H), 4.64–4.54 (m, 1H), 4.34 (dd, J¼15.7, 5.1 Hz,
1H), 3.83 (dd, J¼15.0, 7.7 Hz, 1H), 1.35 (s, 9H); IR (film) nmax 2973,
4.20. 1-(Benzyloxy)-3-((tert-butyloxycarbonyl)amino)-
phenanthrene (30)
2921, 1701, 1591, 1368, 1165, 753 cmꢂ1
.
A solution of 29 (200 mg, 0.6 mmol) in distilled t-BuOH (11 mL)
was treated with distilled Et3N (167
mL, 1.2 mmol) and DPPA
L, 1.2 mmol). The mixture was heated at 80 ꢀC for 9 h then
4.23. 5-(Benzyloxy)-3-(tert-butyloxycarbonyl)-1-
(chloromethyl)-1,2-dihydronaphtho[1,2-e]indole (33)
(258
m
cooled to room temperature and diluted with EtOAc (1 mL). The
solution was washed with saturated aqueous NaHCO3 (2ꢁ10 mL),
H2O (10 mL), and saturated aqueous NaCl (10 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo. Flash chromato-
graphy (SiO2, 1ꢁ11 cm, 2–10% EtOAc–hexanes gradient) afforded 30
(183 mg, 76%) as an off-white solid. Mp 180–182 ꢀC; 1H NMR
A solution of 32 (20 mg, 40
by three freeze–pump–thaw cycles and treated with AIBN (1 mg,
mol) and Bu3SnH (13 L, 50 mol). A stream of Ar was bubbled
mmol) in C6H6 (2 mL) was degassed
6
m
m
m
through the solution for 10 min before the reaction vessel was
closed and warmed to 80 ꢀC for 15 h after which an additional
(500 MHz, CDCl3)
d
8.56 (d, J¼7.7 Hz, 1H), 8.21 (s, 1H), 8.19 (d,
amount of Bu3SnH (13 mL, 50 mmol) and AIBN (1 mg, 6 mmol) were
J¼8.8 Hz,1H), 7.86 (d, J¼8.8 Hz,1H), 7.62 (d, J¼9.1 Hz,1H), 7.60–7.55
added. The mixture was stirred for 3 h at 80 ꢀC before being cooled
to 23 ꢀC and concentrated in vacuo. Flash chromatography (SiO2,
3ꢁ20 cm, 2–10% EtOAc/hexanes gradient) afforded 33 (9 mg, 48%)
(m, 4H), 7.44 (app t, J¼7.7 Hz, 2H), 7.39–7.33 (m, 2H), 6.80 (br s, 1H),
5.23 (s, 2H), 1.59 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 155.6, 152.8,
137.3, 136.9, 132.6, 132.0, 129.5, 128.6, 128.5, 128.0, 127.5, 126.7,
126.1, 124.5, 123.3, 122.1, 120.3, 119.7, 80.7, 70.4, 28.4 (3C); IR (film)
as an off-white solid. 1H NMR (500 MHz, CDCl3)
d
8.06 (d, J¼8.8 Hz,
nmax 3297, 2975, 1690, 1581, 1540, 1509, 1266, 1157, 815, 748 cmꢂ1
;
1H), 7.93 (d, J¼7.0 Hz, 1H), 7.81 (d, J¼8.0 Hz, 1H), 7.62 (app t,
J¼7.7 Hz, 1H), 7.59–7.53 (m, 4H), 7.45 (app t, J¼7.0 Hz, 2H), 7.38–
7.36 (m, 1H), 5.30 (s, 2H), 4.59 (t, J¼9.2 Hz, 1H), 4.39 (d, J¼8.8 Hz,
1H), 4.16 (t, J¼9.7 Hz, 1H), 3.92 (d, J¼11.4 Hz, 1H), 3.36 (t, J¼11.0 Hz,
1H), 1.62 (s, 9H); IR (film) nmax 3467, 2950, 1700, 1644, 1366, 1239,
HRMALDI–FTMS (DHB) m/z 399.1835 (Mþ, C26H25NO3 requires
399.1834).
1163, 1138, 833 cmꢂ1
.
4.21. 1-(Benzyloxy)-4-bromo-3-((tert-butyloxycarbonyl)-
amino)phenanthrene (31)
4.24. seco-N-Boc-iso-CNI (34)
A solution of 30 (100 mg, 0.25 mmol) in THF (6 mL) at ꢂ78 ꢀC
was treated with TsOH (25 mg, 0.13 mmol) in THF (3 mL). NBS
(50 mg, 0.28 mmol) was added and the vial was protected from
light and allowed to stir at ꢂ78 ꢀC for 1 h. The reaction mixture was
warmed to 23 ꢀC and diluted with saturated aqueous NaHCO3
(1 mL). The mixture was diluted with EtOAc (25 mL) and washed
with saturated aqueous NaHCO3 (10 mL), H2O (10 mL), and satu-
rated aqueous NaCl (10 mL). The organic layer was dried (Na2SO4)
and concentrated in vacuo. Flash chromatography (SiO2, 4ꢁ20 cm,
2–5% EtOAc–hexanes gradient) afforded 31 (109 mg, 88%) as
A solution of 33 (20 mg, 0.04 mmol) in 3:1 (v/v) THF–MeOH
(10 mL) was treated with a catalytic amount of 10% Pd/C (20 mg)
and 25% aqueous HCO2NH4 (640 mL, 1.0 mmol). The mixture was
stirred at 23 ꢀC for 48 h, filtered through a Celite plug, and con-
centrated in vacuo. Flash chromatography (SiO2, 1ꢁ10 cm, 10–20%
EtOAc–hexanes gradient) afforded 34 (15 mg, 90%) as a yellow oil.
1H NMR (500 MHz, CDCl3)
d
8.59 (d, J¼8.5 Hz, 1H), 8.17 (d, J¼9.2 Hz,
1H), 7.99 (br s, 1H), 7.91 (d, J¼8.1 Hz, 1H), 7.62 (t, J¼7.0 Hz, 1H), 7.61
(m, 3H), 6.51 (br s, 1H), 4.56 (app t, J¼8.5 Hz, 1H), 4.35 (d, J¼10.5 Hz,
1H), 4.14 (m, 1H), 3.90 (d, J¼10.5 Hz, 1H), 3.35 (t, J¼11.0 Hz, 1H), 1.63
(s, 9H); IR (film) nmax 3349, 2922, 1704, 1596, 1414, 1342, 1254, 1140,
747 cmꢂ1; ESI (negative) m/z 382 (MꢂH, C22H21ClNO3).
a white solid. 1H NMR (500 MHz, CDCl3)
d
9.67 (d, J¼7.7 Hz, 1H),
8.21 (s, 1H), 8.18 (d, J¼9.2 Hz, 1H), 7.82 (d, J¼7.7 Hz, 1H), 7.64 (br s,
1H), 7.59 (d, J¼8.8 Hz, 1H), 7.57–7.51 (m, 4H), 7.42–7.32 (m, 3H),
5.27 (s, 2H), 1.55 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 154.5, 152.7,
136.8, 136.6, 134.2, 129.8, 129.4, 128.6, 128.3, 128.1, 127.8, 127.4,
126.9, 125.8, 124.4, 122.0, 120.0, 101.3, 99.6, 81.2, 70.7, 28.4 (3C); IR
(film) nmax 3405, 2912, 1733, 1600, 1523, 1482, 1221, 1149, 810,
4.25. Resolution of 34
749 cmꢂ1
;
HRMALDI–FTMS (DHB) m/z 500.0845 (MþNaþ,
The enantiomers of 34 were resolved on a HPLC semipreparative
Diacel Chiralcel OD column (10
hexane eluant (8 mL/min). The enantiomers eluted with retention
C26H24BrNO3 requires 500.0837).
m
m, 2ꢁ25 cm) using 5% i-PrOH–
For isomer (10 mg, 8%): 1H NMR
d
8.74–7.72 (m, 1H), 8.15 (d,
J¼8.0 Hz, 1H), 8.04–7.85 (m, 4H), 7.74–7.38 (m, 6H), 7.03 (br s, 1H),
4.84 (t, J¼10.6 Hz, 2H), 1.67 (s, 9H); HRMALDI–FTMS (DHB) m/z
500.0843 (MþNaþ, C26H24BrNO3 requires 500.0837).
times of 18.5 min (natural enantiomer) and 13.9 min (unnatural
23
enantiomer,
a¼1.33). Compound (1S)-34: [
a
]
D
ꢂ50 (c 0.01, THF);
23
(1R)-34: [a]
D
þ50 (c 0.01, THF).

6598
C.M. Gauss et al. / Tetrahedron 65 (2009) 6591–6599
4.26. 3-(tert-Butyloxycarbonyl)-1,2,11,11a-tetrahydrocyclo-
propa[c]naphtho[1,2-e]indol-4-one (N-Boc-iso-CNI, 35)
constants for were determined from the slope of the line obtained
from the least-squares treatment (r2¼0.98) of the plot of ln[(AfꢂAi)/
(AfꢂA)] versus time.
A sample of 34 (2 mg, 5
DMF (250
L) under Ar and cooled to 0 ꢀC. NaH (60% suspension in
mineral oil, 600 g, 15 mol) was added and the mixture was stirred
for 30 min. At this time, the reaction was quenched with the addition
of pH 7.0 phosphate buffer (300 L) and diluted with H2O (1 mL) and
mmol) was dissolved in 3:1 (v/v) THF–
Acknowledgements
m
m
m
We gratefully acknowledge the financial support of NIH
(CA41986) and the Skaggs Institute for Chemical Biology. K.S.M. is
a Skaggs fellow.
m
EtOAc (5 mL). The organic layer was collected, dried (Na2SO4), and
concentrated in vacuo. PTLC (SiO2, 10ꢁ20 cm, 10% EtOAc–hexanes)
afforded 35 (1.0 mg, 54%) as a white solid. 1H NMR (600 MHz, CDCl3)
References and notes
d
8.56 (d, J¼8.3 Hz, 1H), 8.07 (s, 1H), 7.82–7.79 (m, 1H), 7.70–7.65 (m,
1. Chidester, C. G.; Krueger, W. C.; Mizsak, S. A.; Duchamp, D. J.; Martin, D. G. J. Am.
Chem. Soc. 1981, 103, 7629; For a detailed discussion of the DNA alkylation se-
lectivity of CC-1065, see: Boger, D. L.; Johnson, D. S.; Yun, W.; Tarby, C. M. Bioorg.
Med. Chem. 1994, 2, 115; Boger; 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.
3H), 6.91 (s, 1H), 3.72 (d, J¼7.5 Hz,1H), 3.65 (m, 2H),1.47 (s, 9H), 0.92
(t, J¼7.5 Hz, 1H), 0.88–0.87 (m, 1H); HRMALDI–FTMS (DHB) m/z
348.1600 (MþHþ, C22H21NO3 requires 348.1594). Compound (þ)-35:
23
23
[a
]
þ75 (c 0.1, CHCl3); (ꢂ)-35: [
a
]
ꢂ75 (c 0.1, CHCl3).
D
D
2. Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano, K.; Kawamoto,
I.; Tomita, F.; Nakano, H. J. Antibiot. 1988, 41, 1915; Duocarmycin A DNA alkyl-
ation properties: Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Munk, S. A.; Kitos, P.
A.; Suntornwat, O. J. Am. Chem. Soc. 1990, 112, 8961; Boger, D. L.; Ishizaki, T.;
Zarrinmayeh, H. J. Am. Chem. Soc. 1991, 113, 6645; Boger, D. L.; Yun, W.; Ter-
ishima, S.; Fukuda, Y.; Nakatani, K.; Kitos, P. A.; Jin, Q. Bioorg. Med. Chem. Lett.
1992, 2, 759; See also: Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem.
Soc. 1997, 119, 311 and 1996, 118, 2109.
3. Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.; Kawamoto, I.; Yasuzawa,
T.; Takahashi, I.; Nakano, H. J. Antibiot. 1990, 43, 1037; Duocarmycin SA DNA
alkylation properties: Boger, D. L.; Johnson, D. S.; Yun, W. J. Am. Chem. Soc. 1994,
116, 1635; Boger, D. L.; Yun, W. J. Am. Chem. Soc. 1993, 115, 9872; MacMillan, K.
S.; Boger, D. L. J. Am. Chem. Soc. 2008, 130, 16521.
4.27. seco-iso-CNI-TMI (36)
A sample of 35 (1.55 mg, 5.5
m
mol) was treated with 4 N HCl/
EtOAc (100
moved under a stream of N2 and dried under high vacuum for
30 min. The gray residue was dissolved in DMF (60 L) and treated
with 5,6,7-trimethoxyindole-2-carboxylic (1.37 mg,
acid28
5.5 mol) and EDCI (3.15 mg, 16 mol). The mixture was stirred
m
L) and stirred at 23 ꢀC for 1 h. The solvent was re-
m
m
m
under Ar at 23 ꢀC for 18 h in the absence of light before the solvent
was removed under a stream on N2. PTLC (SiO2, 20ꢁ20 cm, 50%
EtOAc–hexanes) afforded 36 (1.6 mg, 57%) as a white solid. 1H NMR
4. Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.; Ogawa, T.; Takahashi, K.;
Sano, H.; Saitoh, Y. Chem. Pharm. Bull. 1995, 43, 378.
5. Igarashi, Y.; Futamata, K.; Fujita, T.; Sekine, A.; Senda, H.; Naoki, H.; Furumai,
T. J. Antibiot. 2003, 56, 107; Structure correction: Tichenor, M. S.; Kastrinsky,
D. B.; Boger, D. L. J. Am. Chem. Soc. 2004, 126, 8396; DNA alkylation properties:
Parrish, J. P.; Kastrinsky, D. B.; Wolkenberg, S. E.; Igarashi, Y.; Boger, D. L. J. Am.
Chem. Soc. 2003, 125, 10971; Trzupek, J. D.; Gottesfeld, J. M.; Boger, D. L. Nat.
Chem. Biol. 2006, 2, 79; Tichenor, M. S.; Trzupek, J. D.; Kastrinsky, D. B.; Shiga,
F.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 15683; Tichenor, M. S.;
MacMillan, K. S.; Trzupek, J. D.; Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem.
Soc. 2007, 129, 10858.
6. Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed. 1996, 35, 1438; For additional
reviews, see: Tichenor, M. S.; Boger, D. L. Nat. Prod. Rep. 2008, 25, 220; 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.
7. Warpehoski, M. A.; Hurley, L. H. Chem. Res. Toxicol. 1988, 1, 315.
8. Boger, D. L.; Garbaccio, R. M. Bioorg. Med. Chem. 1997, 5, 263.
(500 MHz, CDCl3)
d 9.73 (br s, 1H), 9.51 (s, 1H), 8.68 (s, 1H), 8.33
(d, J¼8.8 Hz, 1H), 8.29 (d, J¼7.4 Hz, 1H), 7.94 (d, J¼7.4 Hz, 1H), 7.68
(d, J¼8.8 Hz, 1H), 7.60 (t, J¼7.4 Hz, 1H), 7.54 (t, J¼7.4 Hz, 1H), 6.74
(s, 1H), 6.54 (s, 1H), 4.71 (app d, J¼9.9 Hz, 1H), 4.60 (app t, J¼8.1 Hz,
1H), 4.46 (m, 1H), 4.18 (s, 3H), 4.00 (s, 3H), 3.87 (s, 3H), 3.69 (m, 1H),
3.24 (t, J¼11.4 Hz, 1H); IR (film) nmax 3411, 2959, 1591, 1454, 1412,
1318, 1260, 1107, 1050, 803 cmꢂ1; HRMALDI–FTMS (DHB) m/z
516.1430 (Mþ, C29H25ClN2O5 requires 516.1452). Compound (1S)-
23
23
36: [
a
]
þ17 (c 2.0, CH2Cl2); (1R)-36: [
a]
ꢂ17 (c 1.0, CH2Cl2).
D
D
4.28. iso-CNI-TMI (37)
9. Boger, D. L.; Garbaccio, R. M. Acc. Chem. Res. 1999, 32, 1043.
10. Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002, 102, 2477; Tse, W.; Boger, D. L.
Chem. Biol. 2004, 11, 1607.
A sample of 36 (7.1 mg, 13.7
m
mol) was dissolved in freshly
distilled CH3CN (140
mL) under Ar. Anhydrous DBU (10
m
L, 68 mol)
m
11. Ambroise, Y.; Boger, D. L. Bioorg. Med. Chem. Lett. 2002, 12, 303; Boger, D. L.;
Garbaccio, R. M. J. Org. Chem. 1999, 64, 5666; Boger, D. L.; Santillan, A., Jr.;
Searcey, M.; Jin, Q. J. Am. Chem. Soc. 1998, 120, 11554; Boger, D. L.; Boyce, C. W.;
Johnson, D. S. Bioorg. Med. Chem. Lett. 1997, 7, 235; Boger, D. L.; Johnson, D. S.
J. Am. Chem. Soc. 1995, 117, 1443; Boger, D. L.; Munk, S. A.; Zarrinmayeh, H. J. Am.
Chem. Soc. 1991, 113, 3980; Boger, D. L.; Coleman, R. S.; Invergo, B. J.; Zarrin-
mayeh, H.; Kitos, P. A.; Thompson, S. C.; Leong, T.; McLaughlin, L. W. Chem. Biol.
Interact. 1990, 73, 29; Boger, D. L.; Munk, S. A.; Zarrinmayeh, H.; Ishizaki, T.;
Haught, J.; Bina, M. Tetrahedron 1991, 47, 2661.
12. 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.
13. Boger, D. L.; Hertzog, D. L.; Bollinger, B.; Johnson, D. S.; Cai, H.; Goldberg, J.;
Turnbull, P. J. Am. Chem. Soc. 1997, 119, 4977.
was added at 23 ꢀC, and the mixture was stirred for 1 h. The re-
action mixture was then concentrated under a stream of N2 and
applied directly to PTLC (SiO2, 10ꢁ20 cm, 50% EtOAc–hexanes) to
afford 37 (4.0 mg, 60%) as a white solid. 1H NMR
d 10.50 (br s, 1H),
8.55 (d, J¼8.2 Hz, 1H), 8.06 (s, 1H), 7.85–7.80 (m, 1H), 7.70–7.65 (m,
3H), 7.17 (s, 1H), 6.04 (s, 1H), 6.90 (s, 1H), 4.18 (s, 3H), 4.00 (s, 3H),
3.85 (s, 3H), 3.70 (d, J¼7.5 Hz, 1H), 3.65 (m, 2H), 0.90 (s, J¼7.5 Hz,
1H); HRMALDI–FTMS (DHB) m/z 481.1759 (MþHþ, C29H24N2O5 re-
23
quires 481.1758). Compound (þ)-37: [
a
]
þ125 (c 0.1, THF); (ꢂ)-37:
D
23
[
a]
ꢂ120 (c 0.1, THF).
D
14. Boger, D. L.; Turnbull, P. J. Org. Chem. 1997, 62, 5849; Boger, D. L.; Turnbull, P.
J. Org. Chem. 1998, 63, 8004.
15. Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A. Chem. Rev.1997, 97, 787.
16. Parrish, J. P.; Hughes, T. V.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2004, 126, 80.
17. For related studies, see: Boger, D. L.; Ishizaki, T. Tetrahedron Lett. 1990, 31, 793;
Boger, D. L.; Munk, S. A.; Ishizaki, T. J. Am. Chem. Soc. 1991, 113, 2779; Boger, D. L.;
Yun, W. J. Am. Chem. Soc. 1994, 116, 5523; Boger, D. L.; Yun, W. J. Am. Chem. Soc.
1994, 116, 7996; Boger, D. L.; Santillan, A., Jr.; Searcey, M.; Brunette, S. R.;
Wolkenberg, S. E.; Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000, 65, 4101.
18. Boger, D. L.; Ishizaki, T.; Wysocki, R. J., Jr.; Munk, S. A.; Kitos, P. A.; Suntornwat,
O. J. Am. Chem. Soc. 1989, 111, 6461; Boger, D. L.; Ishizaki, T.; Kitos, P. A.; Sun-
tornwat, O. J. Org. Chem. 1990, 55, 5823.
19. Boger, D. L.; Yun, W.; Teegarden, B. R. J. Org. Chem. 1992, 57, 2873; Boger, D. L.;
McKie, J. A. J. Org. Chem. 1995, 60, 1271; Boger, D. L.; McKie, J. A.; Boyce, C. W.
Synlett 1997, 515; Kastrinsky, D. B.; Boger, D. L. J. Org. Chem. 2004, 69, 2284.
20. Boger, D. L.; Munk, S. A. J. Am. Chem. Soc. 1992, 114, 5487.
21. Gallagher, P. T.; Hicks, T. A.; Lightfoot, A. P.; Owten, W. M. Tetrahedron Lett. 1994,
35, 289; For implementation in related studies, see: Boger, D. L.; McKie, J. A.;
Cai, H.; Cacciari, B.; Baraldi, P. G. J. Org. Chem. 1996, 61, 1710; Boger, D. L.; Han,
4.29. Aqueous solvolysis reactivity: pH 3
Compounds 22 and 35 (50 g) were dissolved in CH3OH (1.5 mL)
m
and mixed with pH 3 aqueous buffer (1.5 mL). The buffer contained
4:1:20 (v:v:v) 0.1 M citric acid, 0.2 M Na2HPO4, and deionized H2O,
respectively. Immediately after mixing, the UV spectra of the so-
lution were measured against a reference solution containing
CH3OH (1.5 mL) and the aqueous buffer (1.5 mL), and this reading
was used as the initial absorbance value. The solution was stop-
pered, protected from light, and allowed to stand at 25 ꢀC. The UV
spectra were recorded at regular intervals until a constant value
was obtained for the long-wavelength absorbance. The increase of
the absorbance at 230 nm was monitored. The solvolysis rate

C.M. Gauss et al. / Tetrahedron 65 (2009) 6591–6599
6599
N.; Tarby, C. M.; Boyce, C. W.; Cai, H.; Jin, Q.; Kitos, P. A. J. Org. Chem. 1996, 61,
4894; Tichenor, M. S.; MacMillan, K. S.; Stover, J. S.; Wolkenberg, S. E.; Pavani,
M. G.; Zanella, L.; Zaid, A. N.; Spalluto, G.; Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am.
Chem. Soc. 2007, 129, 14092.
25. 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;
Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1988, 110, 4796; Boger, D. L.; Co-
leman, R. S. J. Am. Chem. Soc. 1988, 110, 1321; Boger, D. L.; Coleman, R. S. J. Am.
Chem. Soc. 1987, 109, 2717.
26. Boger, D. L.; Machiya, K.; Hertzog, D. L.; Kitos, P. A.; Holmes, D. J. Am. Chem. Soc.
1993, 115, 9025; Boger, D. L.; Machiya, K. J. Am. Chem. Soc. 1992, 114, 10056;
Tichenor, M. S.; Trzupek, J. D.; Kastrinsky, D. B.; Shiga, F.; Hwang, I.; Boger, D. L.
J. Am. Chem. Soc. 2006, 128, 15683.
22. Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Searcey, M. Tetrahedron Lett. 1998,
39, 2227.
23. Interestingly, the substrates bearing a C1–I as well as a C1–H (vs 13) prefer-
entially cyclized to the phenanthrene skeleton.
24. The structure of 33 was confirmed with
a single crystal X-ray structure
determination of red prisms (EtOAc–hexane) of the corresponding methox-
ycarbonyl derivative prepared by acid-catalyzed Boc deprotection (4 N HCl–
EtOAc, 25 ꢀC, 30 min) and treatment with ClCO2Me (THF, NaHCO3, 67%).
27. Boger, D. L.; Yun, W. J. Am. Chem. Soc. 1994, 11, 7996.
28. Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Kitos, P. A.; Suntornwat, O. J. Org.
Chem. 1990, 55, 4499.