Aryl amidation routes to dihydropyrrolo[3,2-e]indoles and pyrrolo[3,2-f]tetrahydroquinolines: Total synthesis of the (±)-CC-1065 CPI subunit

Article abstract of DOI:10.1021/jo062064j

CC-1065 and the related duocarmycins are members of a structurally unique family of naturally occurring molecules and remain some of the most rigorously studied antitumor compounds to date. Herein we describe a total synthesis of the (±)-CC-1065 CPI subun

Full text of DOI:10.1021/jo062064j

Aryl Amidation Routes to Dihydropyrrolo[3,2-e]indoles and
Pyrrolo[3,2-f]tetrahydroquinolines: Total Synthesis of the
(()-CC-1065 CPI Subunit
Michael D. Ganton and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London, Ontario, Canada, N6A 5B7
makerr@uwo.ca
ReceiVed October 5, 2006
CC-1065 and the related duocarmycins are members of a structurally unique family of naturally occurring
molecules and remain some of the most rigorously studied antitumor compounds to date. Herein we
describe a total synthesis of the (()-CC-1065 CPI subunit in an overall yield of 9.3% from commercially
available 5-fluoro-2-nitrophenol. The key steps of this synthesis are a Diels-Alder reaction of an
o-benzoxy-monoimine quinoid and an intramolecular aryl triflate amidation, which formed the pyrrolo-
[3,2-f]tetrahydroquinoline intermediate en route to CPI.
Introduction
unit for simplicity, and boasts an unprecedented and potentially
reactive pyrrolo-fused cyclopropane which is bonded directly
at C4 of the pyrrole and fused to a hexadienone moiety. The
natural enantiomer of CC-1065 has the 8bR,9aS stereochemical
orientation of the cyclopropane ring in the CPI subunit
(Figure 1).2
Over the past two decades CC-1065 and related compounds
have received intense scrutiny as antitumor agents. Their
derivatives remain as some of the strongest candidates for new
exceptionally potent and highly selective therapeutic agents
against tumorgenic cells.
Several syntheses of the CC-1065 CPI subunit have been
accomplished,1 although Tietze’s elegant synthesis of protected
CPI by two metal-mediated cyclizations constitutes the most
expedient route to this molecule.3 Pertinent to this study is
Kraus’ imaginative synthesis of protected CPI through a
Plieninger indolization.4 Preparation of the N,N′-unprotected CPI
subunit, which is useful for the total synthesis of CC-1065, has
been demonstrated only a few times.5 Related compounds
(Figure 1), such as duocarmycin A (2) and duocarmycin SA
(3), have been synthesized numerous times6 and studied
extensively by Boger and co-workers.6c,d More recently, the
absolute configuration, structural revision, and first total syn-
thesis of a similar antitumor compound called yatakemycin (4)
CC-1065 was isolated from cultures of Streptomyces zelensis
(S. zelensis) at Upjohn in 1978, and the structure was disclosed
in 1980.1 Subsequently, it was found that CC-1065 exhibited a
20 pM cytotoxicity against tumorgenic cells. Comparatively,
this activity was approximately 103 times greater than classical
DNA intercalating agents, such as Adriamycin.1 Structurally,
CC-1065 (1, Figure 1) consists of two identical central and
eastern pyrrolo[3,2-e]indole subunits linked together to the
western subunit by amide bonds through the pyrrolidine
nitrogen. The western portion is referred to as the 1,2,8,8a-
tetrahydrocyclopropa[c]pyrrolo[3,2-e]indol-4-one, or CPI sub-
(1) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A. Chem.
ReV. 1997, 97, 787-828.
(4) (a) Kraus, G. A.; Yue, S.; Sy, J. J. Org. Chem. 1985, 50, 283-284.
(b) Kraus, G. A.; Yue, S. J. Chem. Soc., Chem. Commun. 1983, 1198-
1199.
(5) (a) Magnus, P.; Gallagher, T.; Schultz, J.; Or, Y.-S.; Ananthanarayan,
T. P. J. Am. Chem. Soc. 1987, 109, 2706-2711. (b) Moody, C. J.; Pass,
M.; Rees, C. W.; Tojo, G. J. Chem. Soc., Chem. Commun. 1986, 14, 1062-
1063.
(2) Martin, D. G.; Kelly, R. C.; Watt, W.; Wicnienski, N.; Mizsak,
S. A.; Nielsen, J. W. Prairie, M. D. J. Org. Chem. 1988, 53, 4610-4613.
(3) (a) Tietze, L. F.; Buhr, W.; Looft, J.; Grote, T. Chem. Eur. J. 1998,
4, 1554-1560. (b) Tietze, L. F.; Buhr, W. Angew. Chem., Int. Ed. 1995,
34, 1366-1368. (c) Tietze, L. F.; Grote, T. Chem. Ber. 1993, 126, 2733-
2737. (d) Tietze, L. F.; Grote, T. J. Org. Chem. 1994, 59, 192-196.
10.1021/jo062064j CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/15/2006
574
J. Org. Chem. 2007, 72, 574-582

Total Synthesis of the (()-CC-1065 CPI Subunit
SCHEME 1. Initial Retrosynthesis of CC-1065 CPI
SCHEME 2. Synthesis of Quinone Mono-imine 10
FIGURE 1. CC-1065 and related spirocyclopropyl dienone containing
compounds.
was accomplished by Boger and co-workers.7 This synthesis
was followed soon thereafter by Fukuyama and co-workers, who
utilized highly efficient copper-mediated aryl amination proto-
cols to construct the indole and indoline moieties of yatake-
mycin.8
linkage to the other subunits via such sequential intermolecular
domino amidation protocols.
Results and Discussion
We recently disclosed a methodology that allows for the
sequential palladium-catalyzed aryl amidation of trifluoromethane-
sulfonates (triflates) followed by displacement of a phenethyl
carbonate to yield indolines in one pot.9 The scope of this
reaction was fairly general, tolerating a wide array of substitution
patterns on the aryl subunit and a plethora of amide cross-
coupling partners. This is illustrated briefly in eqs 1 and 2 with
selected examples. Most notably and relevant to the synthesis
of CC-1065 and CPI, N-methyl indole-2-carboxamide was found
to be a competent cross-coupling partner with o-trifloxy-
phenethylcarbonate 5a in this domino reaction, forming indoline
6a in good yield (eq 1). Likewise, reaction of 5-trifloxy-4-
ethylindolylcarbonate 5b with benzamide formed the pyrrolo-
[3,2-e]indole 6b in excellent yield (eq 2). Therefore, we reasoned
that it may be possible to access the CPI subunit with an amide
Using this intermolecular amidation protocol as a guide, we
proposed a retrosynthesis as outlined in Scheme 1. The
spirocyclopropyldienone moiety of CPI (7) may be accessed
from a Winstein Ar-3′ alkylation10 of pyrrolo[3,2-e]indole 8
arising from a suitable domino amidation precursor derived from
the 5-trifloxy-7-benzoxy indole 9. This indole could, in turn,
be accessed from a suitably functionalized dihydronaphthalene
obtained from a Diels-Alder cycloaddition of a 1,4-substituted
butadiene and the quinone mono-imine 10.11
(6) (a) Hiroya, K.; Matsumoto, S.; Sakamoto, T. Org. Lett. 2004, 6,
2953-2956. For an excellent enantioselective synthetic route to duocar-
mycins A and SA, see: (b) Yamada, K.; Kurokawa, T.; Tokuyama, H.;
Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 6630-6631. (c) Boger, D. L.;
McKie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem. Soc. 1997, 119, 311-325.
(d) Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem. Soc.
1996, 118, 2301-2302. See also ref 1 for earlier examples of the total
synthesis of these molecules.
Our synthesis of the quinone mono-imine 10 (Scheme 2)
commenced with commercially available 5-fluoro-2-nitrophenol,
which was alkylated with benzyl bromide and subjected to SN-
(7) For the total synthesis, see: (a) Tichenor, M. S.; Kastrinsky, D. B.;
Boger, D. L. J. Am. Chem. Soc. 2004, 126, 8396-8398. For biological
activity studies, see: (b) Parrish, J. P.; Kastrinsky, D. B.; Wolkenberg,
S. E.; Igarashi, Y.; Boger, D. L. J. Am. Chem. Soc. 2003, 125, 10971-
10976.
(8) Okano, K.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2006,
128, 7136-7137.
(9) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7, 4777-4779.
(10) Baird, R.; Winstein, S. J. Am. Chem. Soc. 1963, 85, 567-578.
(11) For Diels-Alder reactions of quinone-monoimines and indole
formation from the resulting dihydronaphthalenes, see: (a) England, D. B.;
Kerr, M. A. J. Org. Chem. 2005, 70, 6519-6522. For previous examples
of this methodology in natural product synthesis, see: (b) England, D. B.;
Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 2209-2212. (c) Jackson,
S. K.; Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7, 1215-1218.
J. Org. Chem, Vol. 72, No. 2, 2007 575

Ganton and Kerr
SCHEME 4. Attempted Dihydropyrrolo[3,2-e]indole
SCHEME 3. Synthesis of 5-Trifloxyindole (17a/b)
Synthesis
closed previously from our group.11a,17 Triflation using NaH/
PhNTf2 of either the TBDPS and the MOM-protected dihy-
dronaphthalenes (Scheme 3) occurred without consequence to
afford triflated compounds 16a and 16b, respectively. This was
14
followed by dihydroxylation,18 and silica-supported NaIO4
mediated oxidative cleavage of the resulting diol to yield a
hemiaminal, which was dehydrated using an excess of MsCl/
NEt3 to afford 17a and 17b in 78% and 86% yields, respectively,
as overall yields for three steps from the triflated dihydronaph-
thalenes 16a/b.
Ar conditions, thereby affording 11.12 The resulting p-nitro-
phenol 11 was reduced using nickel boride13 and immediately
tosylated to stabilize the resulting electron-rich and therefore
unstable aniline. The N-tosylated p-aminophenol 13 was then
easily oxidized using silica-supported sodium periodate11a,14 to
10 in 5 steps and an overall yield of 74% from 5-fluoro-2-
nitrophenol.
Following borohydride reduction of these aldehyde-containing
indoles, (Scheme 4) and protection with methyl chloroformate
to yield 18a and 18b, we were ready to investigate formation
of a dihydropyrrolo[3,2-e]indole through our domino amidation
sequence.9 Unfortunately, in both cases the dihydrofurano[3,2-
e]indole products 19a and 19b were formed exclusively, likely
as a result of triflate cleavage followed by intramolecular SN2
attack of the unmasked phenolate on the carbonate leaving
group. The bulky TBDPS protecting groups may have caused
steric crowding around the triflate cross-coupling partner,
leading to inefficient oxidative addition and thereby allowing
for the competitive side reaction of the phenolate to occur
instead. With this in mind, we attempted the reaction with the
MOM-protected substrate; however, the same result was
obtained. After extensive variation of reaction conditions, no
improvement was observed and we were forced to conclude
that any branching â to the carbonate on such substrates
prohibits the desired cross-coupling event. The reasons for this
are unclear to us at this time.
We then turned our attention to an intramolecular variant of
the Buchwald-Hartwig aryl amination protocol.19a,b Having
obtained a larger quantity of the MOM-protected indole-
aldehyde 17b, we proceeded to perform a reductive amination
using the HCl salt of benzylamine to afford secondary amine
20 (Scheme 5). This process was then followed by intramo-
lecular aryl amination, which proceeded in moderate to good
yields of the required dihydropyrrolo[3,2-e]indole 21. We were
now faced with a protecting group predicament. Any attempt
to selectively manipulate the dual MOM ethers met with little
success. Moreover, de-tosylation by various methods at any
While this dienophile readily underwent a Diels-Alder
reaction with common dienes such as piperylene, we wished to
investigate a more convergent route to CPI which incorporated
a symmetrical diene, allowing for substitution at the 3 position
of indole, and a protected 3-hydroxy-2-indolo-propanal moiety
at the 4 position of the indole. To this end, we chose a protected
hexa-2,4-diene-1,6-diol, previously reported by Roush et al.15
For our purposes, the TBDPS ether or the MOM ether (14a or
14b, respectively) was found to be the most robust (Scheme
3). Upon attempted cycloaddition of either diene with the
dienophile 10, we found that classical conditions (room tem-
perature, reflux, microwave heating, and Lewis acids in a variety
of solvents) were inadequate to yield the required Diels-Alder
adducts. Fortunately, treatment of dienes 14a and 14b with 10
at high pressure16 was found to be effective in producing adducts
15a and 15b in 80% and 92% yields, respectively, after re-
aromatization with DBU.
Having secured a route to these highly functionalized
dihydronaphthalenes, we embarked upon the synthesis of the
required indole using modifications of the methodology dis-
(12) Otten, P. A.; London, R. E.; Levy, L. A. Bioconjugate Chem. 2001,
12, 76-83.
(13) For selective aryl nitro group Ni2B reductions in the presence of
halogens, see: (a) Seltzman, H. H.; Berrang, B. D. Tetrahedron Lett. 1993,
34, 3083-3086. (b) Nose, A.; Kudo, T. Chem. Pharm. Bull. 1989, 37,
816-818.
(14) Zhong, Y. L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
(15) Roush, W. R.; Reilly, M. L.; Koyama, K.; Brown, B. B. J. Org.
Chem. 1997, 62, 8708-8721 and references therein.
(17) (a) Zawada, P. V.; Banfield, S. C.; Kerr, M. A. Synlett 2003, 7,
971-974. (b) Banfield, S. C.; England, D. B.; Kerr, M. A. Org. Lett. 2001,
3, 3325-7.
(18) A significant rate enhancement was observed with certain tertiary
amines, as per the recent findings of Yu, et al., see: Yu, W.; Kang, Y.;
Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217-3219.
(16) For some literature on the subject of high-pressure reactions, see:
(a) Kla¨rner, F.-G.; Diedrich, M. K.; Wigger, A. E.; Jurczak, J.; Gryko,
D. T. In Chemistry Under Extreme or Non-Classical Conditions; van Eldik,
R., Hubbard, C. D., Eds.; Wiley: New York, 1997; Chapters 3 and 4, pp
103-188. (b) Isaacs, N. S. In High-Pressure Techniques in Chemistry and
Physics; Holzapfel, W. B., Isaacs, N. S., Eds.; Oxford University Press:
New York, 1997; Chapter 7, pp 307-309.
(19) (a) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron.
1996, 52, 7525-7546. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin,
J.; Buchwald, S. L. J. Org. Chem. 2000, 1158-1174. (c) Yin, J.; Buchwald,
S. L. Org. Lett. 2000, 2, 1101-1104. (d) The intramolecular aryl amidation
is also known, see: Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-
37. (e) Aoki, K.; Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
3068.
576 J. Org. Chem., Vol. 72, No. 2, 2007

Total Synthesis of the (()-CC-1065 CPI Subunit
SCHEME 5. Synthesis of a Dihydropyrrolo[3,2-e]indole
SCHEME 7. Synthesis of Indole Benzamide 28
SCHEME 6. Revised Retrosynthesis of the CC-1065 CPI
Subunit
hydroxyl group as a TIPS ether 26 (this would later be converted
to a triflate for cross-coupling). Dihydroxylation of the resulting
TIPS-protected naphthol followed by oxidative cleavage and
treatment with a catalytic amount of H2SO4 cleanly led to the
corresponding indole 27 in high yield over four steps. Notably,
we found that this indole only required a simple wash through
a plug of silica in a sintered glass funnel. This purification could
be carried out on scales upward of 20 g with ease. Formation
of 24 with acetone cyanohydrin and triethylamine was then
followed by protection of the resulting secondary alcohol as a
MOM ether using stoichiometric trifluoromethanesulfonic acid
and dimethoxymethane as the solvent.21 This was the first
instance of flash chromatography in the entire synthesis. As
predicted, reduction of the cyanohydrin with an excess of LAH
occurred cleanly with the TIPS-protected phenol. This was
followed by amidation with benzoyl chloride to form the
required amide 28 in good yield.
An exchange of the TIPS protecting group for a triflate
occurred smoothly to afford the indole triflate 29 (Scheme 8).
This intramolecular aryl amidation substrate was then subjected
to standard Buchwald-Hartwig amidation conditions19c-e to
cleanly afford the pyrrolo[3,2-f] tetrahydroquinoline CPI precur-
sor 30 in excellent yield. Although many deprotection strategies
were attempted at this point, we found that only fresh BCl3 in
CH2Cl2 would afford the deprotected CPI precursor 31 in
adequate yield. Although Mitsunobu activation of an alcohol
has been used to affect Winstein Ar-3′ alkylation with a primary
alcohol of the dihydropyrroloindole in many instances, to our
knowledge, the corresponding alkylation of a pyrrolo[3,2-f]-
tetrahydroquinoline to form a CPI precursor has not been
attempted.1 We were pleased to find that this alkylation occurred
stage led to dimer formation, presumably through a gramine-
like fragmentation. Attempts to selectively hydrogenate the
phenolic benzyl group and benzylic MOM ether led to multiple
products which would not converge to a single product (even
if forced using high pressures of H2 and various Pd, Pt, and
other transition-metal catalysts for hydrogenation). We decided
to simplify this process by selectively debenzylating the
dihydropyrrole nitrogen using R-chloroethylchloroformate (ACE-
Cl)20 followed by benzoylation. However, attempts to elaborate
the resulting amide-linked dihydropyrroloindole 22 to CPI met
with negligible success.
The simplest (and most obvious) solution to our protecting
group woes was to use a much simpler diene. We settled upon
piperylene due to the ease with which the corresponding Diels-
Alder occurred and the ability to perform this reaction on tens
of grams per reaction (high pressure was limited to the synthesis
of 1 g of product every 48 h). However, our approach involving
piperylene required a modified retrosynthesis (Scheme 6).
Instead of targeting a dihydropyrroloindole precursor to CPI,
we reasoned that a pyrrolo[3,2-f]tetrahydroquinoline CPI precur-
sor 23 should be easier to access through the cyanohydrin 24,
which could arise from an indole synthesized from piperylene
and our previously described dienophile 10.
The Diels-Alder reaction of dienophile 10 and piperylene
occurred readily at room temperature overnight at scales of up
to 25 g to yield dihydronaphthalene 25 in excellent yield after
a simple trituration (Scheme 7). Since we wished to reduce a
cyanohydrin in subsequent steps, clearly a trifloxy group would
be untenable. Therefore, we decided to protect the naphtholic
(20) (a) Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195-196. (b)
Gubert, S.; Braojos, C.; Sacrista´n, A.; Ortiz, J. A. Synthesis 1991, 1991,
318-319. (c) Olofson, R. A.; Martz, J. T. J. Org. Chem. 1984, 49, 2081-
2082.
(21) David, S.; Thieffry, A.; Veyrie`res, A. J. Chem. Soc., Perkin Trans.
1 1981, 1796.
J. Org. Chem, Vol. 72, No. 2, 2007 577

Ganton and Kerr
SCHEME 8. Completion of the Synthesis of CC-1065 CPI
Subunit
SCHEME 9. Intramolecular Aryl Amidation with a More
Complex Cross-Coupling Partner
Experimental Section
Quinone Mono-imine (10). Refer to the Supporting Information
for experimental details pertaining to the synthesis of p-aminophenol
13 from 12. To a solution of 13 (12.0 g, 32.0 mmol) in 400 mL of
dichloromethane was added 75 g of 0.68 mmol/g of silica-supported
NaIO4, and the mixture was mechanically stirred for 4 h. The
resulting ochre solution was filtered to remove silica and concen-
trated in vacuo to leave 11.47 g (96%) of pale orange solid 10:
readily under standard Mitsunobu conditions to afford 32 in
high yield. We were then faced with our final deprotection of
the tosyl group. Although we were unable to selectively remove
the tosyl in the presence the benzoyl amide, we found that
treatment of 32 under the conditions of Magnus et al. (1 N
NaOMe in methanol overnight) cleanly afforded unprotected
CC-1065 CPI 33 in good yield.5a
1
mp ) 154-156 °C (darkens upon heating). H NMR (400 MHz,
CDCl3) δ 8.08 (d, J ) 9.6, 1H), 7.93 (d, J ) 8.0, 2H), 7.34 (m,
6H), 7.26 (s, 1H), 6.56 (dd, J ) 9.6, 1.6, 1H), 5.95 (d, J ) 1.6,
1H), 5.05 (s, 2H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
186.4, 160.8, 159.5, 144.8, 136.9, 134.7, 134.4, 129.8, 129.0, 128.7,
127.8, 127.2, 109.2, 71.1, 32.2. IR (thin film) ν 3088, 2921, 2853,
1647, 1632, 1595, 1317, 1238, 1154 cm-1. HRMS calcd for C20H17-
NO4S: 367.0878. Found: 367.0880.
While we were cognisant of the fact that we would be unable
to remove the tosyl pyrrole protecting group without rupturing
the amide bond, we thought it would be interesting if we
investigated more complex amides in this intramolecular cross-
coupling reaction. We were particularly interested in use of the
intramolecular reaction with indole-2-carboxamide substrates.
The amide formations with (N-unprotected)indole-2-carbonyl
chloride (compound not shown) and N-methylindole-2-carbonyl
chloride 349 were facile, and elaboration to the corresponding
triflates occurred, in both cases, without incident (Scheme 9).
However, we found that the aryl amidation with the indole-N-
unprotected substrate did not occur, even after prolonged
reaction times. However, the N-protected substrate 36, which
was obtained via an exchange of the TIPS protecting group of
compound 35 for a triflate, readily afforded pyrrolo[3,2-f]-
tetrahydroquinoline 37 in an acceptable yield. Although attempts
to elaborate this to a tosyl-protected indole-2-carboxamide-
containing CPI-like molecule were attempted, we found that
any attempt to deprotect the MOM ether led to a complex
mixture, possibly due to competing reaction pathways at the 3
position of the indole-2-carboxamide.
In summary, we developed an efficient synthesis of CC-1065
CPI through an intramolecular aryl amidation that formed the
key pyrrolo[3,2-f]tetrahydroquinoline precursor. This route
allowed access to N,N′-unprotected CPI in a 9.3% overall yield
from commercially available 5-fluoro-2-nitrophenol. Notably,
this yield is competitive with existing syntheses of N,N′-
unprotected CPI.5 Moreover, silica-mediated purification was
not required for the first 10 steps of the synthetic sequence.
Elaboration of unprotected CPI toward a total synthesis of CC-
1065 is underway.
Rearomatized Dihydronaphthol High-Pressure Diels-Alder
Adduct (15a). Refer to the Supporting Information for experimental
details pertaining to the synthesis of diene 14a. Dienophile 10 (50
mg, 0.135 mmol) and diene 14a (84 mg, 0.142 mmol) were added
to high-pressure tubing and dissolved in 2.0 mL of DCM. The
high-pressure tube was sealed with a brass fitting and placed in a
high-pressure reactor (180 000 psi) for 20 h. After this time the
contents of the tube were transferred to a round-bottomed flask
and a catalytic amount of DBU was added. The resulting mixture
was stirred for 30 min, after which time the aromatized adduct was
washed with 5% HCl and re-extracted twice with dichloromethane.
After concentration to a residue, the compound was purified by
flash chromatography (2-20% ethyl acetate in hexanes) to afford,
after rotary evaporation, 0.104 g (80%) yield of dihydronaphthol
15a as an off-white foam: mp ) 122-124 °C. 1H NMR (400 MHz,
CDCl3) δ 8.81 (s, 1H), 7.65-7.62 (m, 2H), 7.56 (d, J ) 8.4, 2H),
7.50-7.48 (m, 3H), 7.42-7.37 (m, 2H), 7.35-7.18 (m, 15H),
7.14-7.09 (m, 5H), 6.98 (d, J ) 8.4, 2H), 6.51 (s, 1H), 5.92 (dd,
J ) 9.2, 5.4,1H), 5.63 (dd, J ) 10.0, 5.4 1H), 4.79 (d, J ) 12.2,
1H), 4.51 (d, J ) 12.2, 1H), 4.47-4.40 (m, 1H), 3.90-3.82 (m,
1H), 3.65 (dd, J ) 10.0, 2.8, 1H), 3.41 (dd, J ) 9.2, 6.0, 1H), 3.26
(t, J ) 8.8, 1H), 3.06 (t, J ) 10.0, 1H), 2.29 (s, 3H), 1.03 (s, 9H),
0.99 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 155.8, 154.8, 14207,
128.5, 137.5, 136.8, 135.8, 135.7, 135.6, 132.9, 130.5, 130.2, 130.0,
129.9, 129.4, 129.0, 128.5, 128.2, 128.0 (2C), 127.9, 127.8, 127.6,
127.2, 125.9, 117.8, 116.7, 101.3, 71.6, 70.1, 39.6, 39.0, 27.0, 26.8,
21.7, 19.3, 19.2. IR (thin film) ν 3289, 2931, 2859, 1654, 1559,
1457, 1113 cm-1. HRMS calcd for C58H63NO6SSi2: 957.3915.
Found: 957.3922.
Rearomatized Dihydronaphthol High-Pressure Diels-Alder
Adduct (15b). Refer to the Supporting Information for experimental
578 J. Org. Chem., Vol. 72, No. 2, 2007

Total Synthesis of the (()-CC-1065 CPI Subunit
details pertaining to the synthesis of diene 14b. Dienophile (10)
(300.0 mg, 0.814 mmol) and 14b (199.0 mg, 0.985) of diene were
added to high-pressure tubing and dissolved in 7.5 mL of DCM.
This was duplicated, and the two high-pressure tubes were sealed
with brass fittings and placed side-by-side in a high-pressure reactor
(180 000 psi) for 24 h. After this time the contents of the tubes
were transferred to a round-bottomed flask, and a catalytic amount
of DBU was added. The resulting mixture was stirred for 30 min,
after which time the aromatized adduct was washed with saturated
ammonium chloride and re-extracted twice with dichloromethane.
After concentration to a residue, the compound was allowed to
solidify overnight and then triturated in diethyl ether to afford 0.860
g (92%) yield of dihydronaphthol 15b as an off-white foam: mp
) 126-128 °C. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.49
(d, J ) 8.4, 2H), 7.34-7.29 (m, 3H), 7.13-7.11 (m, 2H), 6.95 (d,
J ) 8.4, 2H), 6.67 (s, 1H), 6.37 (s, 1H), 6.05 (dd, J ) 10.0, 5.6,
1H), 5.94 (dd, J ) 10.0, 5.6, 1H), 4.72 (d, J ) 12.0, 1H), 4.68-
4.61 (m, 2H), 4.55-4.52 (m, 2H), 4.50-4.46 (m, 1H), 4.35 (d,
J ) 12.0, 1H), 3.88-3.82 (m, 2H), 3.65 (dd, J ) 9.2, 5.6, 1H),
3.49 (dd, J ) 9.2, 5.6, 1H), 3.44 (t, J ) 9.2, 1H), 3.29 (s, 3H),
3.20 (s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 155.3,
154.2, 142.8, 137.8, 137.5, 136.3, 129.4, 128.9, 128.3, 127.8, 127.3,
127.0, 125.7, 118.1, 115.6, 100.8, 96.3, 95.9, 74.2, 72.2, 69.8, 55.7,
55.1, 36.8, 36.7, 21.5. IR (thin film) ν 3269, 2927, 1612, 1596,
1327, 1153 cm-1. HRMS calcd for C30H35NO8S: 569.2083.
Found: 569.2077.
to a Schlenk tube, which had been previously purged and back-
filled with argon three times, was added 0.009 g (0.0741 mmol) of
benzamide cross-coupling partner, 0.028 g (0.0805 mmol) of Cs2-
CO3, 0.003 g (0.0031 mmol) of Pd2(dba)3, and 0.004 g (0.476
mmol) of Xantphos. After addition of these solid reagents, the
Schlenk tube was again purged and back-filled with argon three
times before exchanging a screw cap for a septum and adding the
aryl trifloxy substrate in dioxane by cannula to the Schlenk tube.
The septum was then quickly exchanged for a screw cap, the
Schlenk tube was then placed in a sand bath, and the reaction was
allowed to occur over 40 h. After this time 10 mL of 5% HCl was
added, and the aqueous phase was then washed three times with
diethyl ether. The organic extracts were then washed with brine
and dried over MgSO4 before being concentrated with SiO2 in vacuo
to yield solid supported adduct which was then subjected to column
chromatography (5-35% gradient of ethyl acetate in hexanes) to
yield 30.4 mg (87%) of dihydrofuran 19b as a white foam. 1H NMR
(400 MHz, CDCl3) δ 7.82 (s, 1H), 7.41 (d, J ) 7.6, 2H), 7.31 (s,
3H), 7.16-7.12 (m, 2H), 7.01 (d, J ) 7.6, 2H), 6.21 (s, 1H), 4.92-
4.84 (AB, JAB ) 13.6, 1H), 4.69 (s, 4H), 4.60-4.52 (m, 3H), 4.43
(at, J ) 8.4, 1H), 3.82-3.67 (m, 2H), 3.39 (s, 3H), 3.26 (s, 3H),
2.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.8, 146.8, 143.8,
137.2, 136.1, 129.7, 129.3, 128.8, 127.9, 127.6, 127.0, 115.2, 108.7,
96.4, 95.1, 92.9, 75.6, 70.6, 69.9, 61.4, 55.5, 55.2, 42.3, 21.5. IR
(thin film) ν 2931, 2888, 1609, 1497, 1362, 1040 cm-1. HRMS
calcd for C30H33NO8S: 567.1927. Found: 567.1924.
Dihydrofurano[3,2-e]indole (19a). Refer to the Supporting
Information for experimental details pertaining to the synthesis of
indole-4-ethylcarbonate 18a from 5-trifloxyindole 17a. To the aryl
trifloxy cross-coupling partner 18a (0.116 g, 0.099 mmol) was
added 1.5 mL of dry dioxane. The resulting solution was stirred
with argon purging for 30 min at room temperature to remove any
dissolved gases in the solvent/aryl trifloxy substrate. Meanwhile,
to a Schlenk tube, which had been previously purged and back-
filled with argon three times, was added the benzamide cross-
coupling partner (0.015 g, 0.020 mmol) of 0.045 g (0.139 mmol)
of Cs2CO3 (0.009 g, 0.010 mmol) and Pd2(dba)3 (0.012 g, 0.020
mmol) of Xantphos. After addition of these solid reagents, the
Schlenk tube was again purged and back-filled with argon three
times before exchanging a screw cap for a septum and adding the
aryl trifloxy substrate in dioxane by cannula to the Schlenk tube.
The septum was then quickly exchanged for a screw cap, the
Schlenk tube was then placed in a sand bath, and the reaction was
allowed to occur over 36 h. After this time 10 mL of 5% HCl was
added, and the aqueous phase was then washed three times with
diethyl ether. The organic extracts were then washed with brine
and dried over MgSO4 before being concentrated with SiO2 in vacuo
to yield solid supported adduct which was then subjected to column
chromatography (2-24% gradient of ethyl acetate in hexanes) to
yield 58 mg (71% yield) of dihydrofuran 19a as a white foam. 1H
NMR (400 MHz, CDCl3) δ 7.68 (d, J ) 8.0, 2H), 7.56 (d, J ) 8.0,
2H), 7.49 (t, J ) 4.8, 3H), 7.42-7.20 (m, 20H), 7.02 (d, J ) 8.0,
2H), 6.24 (s, 1H), 4.93 (s, 2H), 4.72-4.68 (m, 2H), 4.60 (d, J )
8.8, 1H), 4.46 (t, J ) 8.0, 1H), 3.84-3.76 (m, 1H), 3.67 (dd, J )
10.0, 4.0, 1H), 3.49 (dd, J ) 10.0, 8.0, 1H), 2.32 (s, 3H), 1.04 (s,
9H), 0.92 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 162.2, 157.9,
146.7, 143.5, 137.4, 136.4, 135.6, 135.4, 133.4 (2C), 133.2, 133.0,
129.8, 129.7, 129.6 (2C), 129.5, 129.2, 128.8, 128.4, 128.1, 127.9,
127.7, 127.6 (3C), 126.9, 123.7, 120.3, 118.8, 109.3, 92.7, 75.2,
70.7, 66.2, 59.1, 44.5, 26.8, 26.7, 21.5, 19.2, 19.1. IR (thin film) ν
) 2925, 2852, 1696, 1540, 1109 cm-1. HRMS calcd for C58H61-
NO6SSi2: 955.3758. Found: 955.3751.
N-Alkyl, N′-Benzylamino-indole (20). Refer to the Supporting
Information for experimental details pertaining to the synthesis of
5-trifloxyindole 17b. Benzylamine hydrochloride was prepared by
adding a 5.7 M solution of dry HCl in diethyl ether to neat
benzylamine. The salt precipitated as a white solid immediately
and after filtration was washed three times with diethyl ether and
dried in vacuo. Benzylamine hydrochloride salt (0.392 g, 2.3 mmol)
was added to a suspension of aldehyde 17b (0.550 g, 0.763 mmol)
in 10 mL of methanol. Sodium cyanoborohydride (0.048 g, 0.763
mmol) was added, and the reaction was stirred at room temperature
for 3 h. The resulting reaction mixture was diluted with ethyl acetate
and washed with saturated NaHCO3, followed by water. Combined
aqueous washes were re-extracted three times with ethyl acetate.
The combined organic phases were washed with brine, dried, and
suspended on 4 g of SiO2 by concentrating in vacuo. This crude,
silica-supported indole was then purified by FCC (elution with a
gradient of 30-50% ethyl acetate in hexanes) to yield 0.433 g (70%
yield) of pure 20 as a light yellow oil. 1H NMR (600 MHz, CDCl3)
δ 8.02 (s, 1H), 7.53 (d, J ) 8.4, 2H), 7.40-7.38 (m, 3H), 7.30-
7.22 (m, 7H), 7.15 (d, J ) 8.4, 2H), 6.67 (s, 1H), 5.00 (s, 2H),
4.98-4.93 (AB, δA ) 4.96, δB ) 4.94, JAB ) 12.0, 2H), 4.78 (d,
J ) 6.6, 1H), 4.74 (d, J ) 6.6, 1H), 4.59-5.56 (AB, δA ) 4.58,
δB ) 4.56, JAB ) 6.6, 2H), 4.02-3.95 (m, 2H), 3.86 (dd, J ) 9.6,
7.8, 1H), 3.79-3.74 (AB, δA ) 3.77, δB ) 3.75, JAB ) 9.2, 2H),
3.45 (s, 3H), 3.24 (s, 3H), 3.16-3.13 (dd, J ) 12.0, 7.2, 1H), 3.09-
3.05 (dd, J ) 12.0, 7.2), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 144.9, 144.6, 144.3, 140.4, 136.8, 135.1, 132.5, 130.9, 129.4,
128.5, 128.4, 128.2, 128.0, 127.8, 127.1, 126.7, 124.4, 119.1, 118.2
[(trifluoromethanesulfonate CF3) q, J ) 318.6], 116.6, 101.8, 96.2,
95.1, 70.9, 69.2, 62.0, 55.5, 55.0, 53.9, 50.6, 40.1, 21.5. IR (thin
film) ν 2925, 1614, 1416, 1215, 1148, 1035 cm-1. HRMS calcd
for C38H41F3N2O10S2: 806.2155. Found: 806.2155.
Dihydropyrrolo[3,2-e]indole (21). To the aryl trifloxy cross-
coupling partner 20 (1.30 g, 1.59 mmol) was added 10.0 mL of
dry dioxane. The resulting solution was stirred with argon purging
for 30 min at room temperature to remove any dissolved gases in
the solvent/aryl trifloxy substrate. Meanwhile, to a Schlenk tube,
which had been previously purged and back-filled with argon three
times, was added Cs2CO3 (0.720 g, 7.22 mmol), Pd2(dba)3, (0.145
g, 0.159 mmol), and di-tert-butylbiphenylphosphine (0.142 g, 0.476
mmol). After addition of these solid reagents, the Schlenk tube was
again purged and back-filled with argon three times before
exchanging a screw cap for a septum and adding the aryl trifloxy
Dihydrofurano[3,2-e]indole (19b). Refer to the Supporting
Information for experimental details pertaining to the synthesis of
indole-4-ethylcarbonate 18b from 5-trifloxyindole 17b. To 0.0483
g (0.062 mmol) of the aryl trifloxy cross-coupling partner 18b was
added 1.5 mL of dry dioxane. The resulting solution was stirred
with argon purging for 30 min at room temperature to remove any
dissolved gases in the solvent/aryl trifloxy substrate. Meanwhile,
J. Org. Chem, Vol. 72, No. 2, 2007 579

Ganton and Kerr
1
substrate in dioxane by cannula to the Schlenk tube. The septum
was then quickly exchanged for a screw cap, the Schlenk tube was
then placed in a sand bath, and the reaction was allowed to occur
over 40 h. After this time 10 mL of 5% HCl was added, and the
aqueous phase was then washed three times with diethyl ether. The
organic extracts were then washed with brine and dried over MgSO4
before being concentrated with SiO2 in vacuo to yield solid
supported adduct which was then subjected to column chromatog-
raphy (5-60% gradient of ethyl acetate in hexanes) to yield 0.887
g (82% yield) of dihydropyrrolo[3,2-e]indole 21 as a light yellow
86-87 °C. H NMR (600 MHz, CDCl3) δ 9.64 (t, J ) 2.4, 1H),
7.63 (d, J ) 9.0, 2H), 7.57 (s, 1H), 7.28-7.22 (m, 3H), 7.16 (d, J
) 9.0, 2H), 7.11 (d, J ) 8.4, 2H), 6.11 (s, 1H), 4.95 (s, 2H), 3.95
(d, J ) 2.4, 2H), 2.34 (s, 3H), 2.33 (s, 3H), 1.00-0.90 (m, 21H).
13C NMR (100 MHz, CDCl3) δ 200.7, 150.6, 145.1, 143.7, 137.8,
136.5, 133.2, 129.3, 128.4, 127.7, 127.6, 127.1, 126.3, 120.4, 115.7,
106.3, 100.6, 69.9, 40.7, 21.5, 17.9, 13.3, 12.8. IR (thin film) ν )
2943, 2867, 1726, 1598, 1494, 1353, 1153 cm-1. HRMS calcd for
C34H43NO5SSi: 605.2631. Found: 605.2628.
Indole Cyanohydrin (24). To indole 27 (2.366 g, 3.9 mmol) of
in 50 mL of dry DCM was added acetone cyanohydrin (0.428 mL,
4.68 mmol) followed by triethylamine (0.652 mL, 4.68 mmol), and
the resulting reaction mixture was stirred for 2 h. After this time
the reaction mixture was partitioned between 5% HCl and diluted
with DCM. The resulting biphasic mixture was extracted, and the
organic phase was washed with saturated sodium bicarbonate,
followed by brine, dried over MgSO4, and concentrated to yield a
light yellow oil, which was used without purification in the next
step. A 2.36 g amount of this residue was taken up in 40 mL of
dimethoxymethane, and 0.559 mL (4.10 mmol) of trifluoromethane-
sulfonic acid was added dropwise under argon. After 1 h saturated
sodium bicarbonate was added, and the mixture was extracted three
times with diethyl ether. The organic phases were washed with
brine, dried over MgSO4, filtered, and concentrated. The resulting
residue was purified by flash chromatography (2-20% ethyl acetate,
2% intervals, 250 mL each) to yield 1.79 g (71% yield over two
1
oil. H NMR (600 MHz, CDCl3) δ 7.83 (s, 1H), 7.51 (d, J ) 8.4,
2H), 7.32-7.22 (m, 8H), 7.15 (m, 2H), 7.08 (d, J ) 8.4, 2H), 6.01
(s, 1H), 4.92-4.85 (AB, δA ) 4.91, δB ) 4.86, JAB ) 12.0, 1H),
4.77-4.75 (m, 4H), 4.64-4.59 (AB, δA ) 4.63, δB ) 4.60, JAB
)
6.0, 2H), 4.24 (d, J ) 15.0, 1H), 3.95 (d, J ) 15.0, 1H), 3.71 (m,
2H), 3.53 (t, J ) 9.6, 2H), 3.45 (s, 3H), 3.31 (s, 3H), 3.23 (t, J )
7.8, 1H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 150.2, 146.5,
143.5, 138.2, 137.5, 136.6, 129.5, 129.2, 128.4, 128.3, 127.8, 127.6,
127.0, 119.3, 115.4, 111.5, 96.3, 95.2, 92.4, 70.5, 69.2, 61.5, 57.9,
55.4, 55.1, 53.9, 40.3, 21.5. IR (thin film) ν 2926, 1599, 1094,
1036 cm-1. HRMS calcd for C37H40N2O7S: 656.2556. Found:
656.2572.
Dihydronaphthol (25). The dienophile 10 (3.25 g, 8.8 mmol)
was dissolved into 60 mL of dichloromethane. Piperylene (3.07
mL, 31 mmol) was then added, and the reaction mixture was stirred
at room temperature for 15 h. At this point the reaction mixture
was concentrated in vacuo to approximately 30 mL of solution,
then 12 drops of DBU were added, and the re-aromatized Diels-
Alder cycloadduct precipitated out of solution after stirring the
mixture at 0 °C over a period of 20 min. Tosic acid was added
until the reaction mixture turned yellow. The resulting neutral
precipitate was filtered and washed with 50 mL of 1:1 methanol to
water. This product was then triturated with chloroform at 0 °C
for 30 min, filtered, and left on the pump to afford 3.08 g (80%
yield) of pure cycloadduct 25 as a white powder: mp ) 195 °C
(dec). 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.83 (s, 1H),
7.36 (d, J ) 8.0, 2H), 7.23 (m, 3H), 7.08 (d, J ) 6.4, 2H), 6.96 (d,
J ) 8.0, 2H), 6.15 (s, 1H), 5.78 (m, 2H), 4.58 (d, J ) 12.8, 1H),
4.20 (d, J ) 12.8, 1H), 3.90 (m, 1H), 3.10 (d, J ) 22, 1H), 2.85
(d, J ) 22, 1H), 2.16 (s, 3H), 1.03 (d, J ) 6.8, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 167.3, 155.1, 154.7, 143.2, 142.2, 140.0,
137.6, 129.3, 128.8, 128.1, 127.5, 127.3, 123.4, 114.1, 113.6, 97.8,
69.2, 30.7, 23.5, 21.6 (2 C). IR (thin film) ν 3415, 3258, 3030,
2960, 2924, 2866, 1593, 1321, 1156 cm-1. HRMS cald for C25H25-
NO4S: 435.1504. Found: 435.1505.
Indole (27). Refer to the Supporting Information for experimental
details pertaining to the synthesis of the dihydronaphthalene 26.
The dihydronaphthalene 26 (2.93 g, 4.95 mmol) was suspended in
a mixture of THF (140 mL) and H2O (60 mL). A crystal of osmium
tetraoxide (∼2 mg) was added, and the mixture was stirred for 30
min, giving a black solution, after which NMO (0.695 g, 5.94 mmol)
was added. The solution was stirred until the starting material was
consumed by TLC (∼15 h), at which point Na2S2O3 (3.74 g, 29.7
mmol) was added and the mixture stirred for a further 30 min. The
mixture was extracted with ethyl acetate, and the aqueous phase
was then re-extracted. Combined extracts were dried and concen-
trated in vacuo to leave the crude diol. The crude diol was used
without further purification and suspended in 100 mL of CH2Cl2,
and NaIO4/SiO2 (10.91 g, 7.43 mmol) was then added. The mixture
was stirred for 2 h, filtered, and concentrated to yield the crude
dialdehyde, which was taken up in 80 mL of dry THF. A 0.743
mmol amount of H2SO4 was then added, and the mixture was stirred
for 5 h. The reaction mixture was then washed with 5% HCl and
extracted with ethyl acetate. Aqueous washes were re-extracted three
times with 10 mL of ethyl acetate, combined with the original
extract, dried, and concentrated to a thick oil. This crude indole
was then purified through a short plug of silica in a sintered glass
funnel (elution with isocratic 30% ethyl acetate in hexanes) to yield
3.00 g (90% over 3 steps) of indole 27 as a white powder: mp )
1
steps) of the cyano-indole 24 as a pale yellow oil. H NMR (600
MHz, CDCl3) δ 7.60 (d, J ) 9.0, 2H), 7.58 (s, 1H), 7.28-7.24 (m,
3H), 7.15 (d, J ) 9.0, 2H), 7.08-7.06 (m, 2H), 6.06 (s, 1H), 4.97-
4.92 (AB, δA ) 4.95, δB ) 4.94, JAB ) 13.8, 2H), 4.70 (d, J )
6.6, 1H), 4.59 (dd, J ) 9.0, 6.0, 1H), 4.45 (d, J ) 6.6, 1H), 3.50
(dd, J ) 13.8, 9.6, 1H), 3.41 (dd, J ) 13.8, 6.0, 1H), 2.95 (s, 3H),
2.48 (s, 3H), 2.34 (s, 3H), 1.03-0.93 (m, 21H). 13C NMR (100
MHz, CDCl3) δ 150.6, 145.0, 143.6, 137.8, 133.5, 129.2, 128.4,
127.8, 127.7, 127.0, 126.3, 120.4, 118.5, 116.3, 109.1, 100.6, 95.3,
70.0, 64.4, 55.6, 29.8, 21.5, 17.9, 13.7, 12.9. IR (thin film) ν 2931,
1597, 1153, 1028 cm-1. HRMS calcd for C37H48N2O6SSi: 676.3002.
Found: 676.3005.
Indole Benzamide (28). To the cyano-indole 24 (1.39 g, 2.05
mmol) in 20 mL of dry diethyl ether was added powdered lithium
aluminum hydride (LAH) (0.311 g, 8.20 mmol) portion-wise at 0
°C. After completion of the addition of LAH, the reaction mixture
was warmed to room temperature and 1 N NaOH was added
dropwise, after 20 min, until a white precipitate formed. The
reaction mixture was then filtered over celite and concentrated to
yield a residue which was immediately taken up in 20 mL of dry
THF. To this solution was added triethylamine (0.541 mL, 3.89
mmol), followed by benzoyl chloride (0.226 mL, 1.94 mmol). This
reaction mixture was stirred for 22 h, at which point 50 mL of 1 N
NaOH was added, and the biphasic mixture was then stirred
vigorously for 1 h. After this time the mixture was extracted twice
with ethyl acetate, washed with brine, dried over MgSO4, and
concentrated to yield a residue. The residue was purified by flash
chromatography (2-30% ethyl acetate:hexanes gradient) to yield,
after concentration of the pure fractions, 1.17 g (81% yield over
two steps) of the white, crystalline solid 28: mp ) 86-87 °C. 1H
NMR (400 MHz, CDCl3) δ 7.75 (d, J ) 7.2, 2H), 7.62 (d, J ) 8.0,
2H), 7.55 (s, 1H), 7.46-7.42 (m, 1H), 7.37 (t, J ) 8.0, 2H), 7.30-
7.26 (m, 2H), 7.14 (d, J ) 7.2, 2H), 7.13-7.07 (m, 3H), 6.08 (s,
1H), 5.00-4.91 (AB, δA ) 4.97, δB ) 4.93, JAB ) 13.6, 2H), 4.42
(d, J ) 6.4, 1H), 4.18 (d, J ) 6.4, 1H), 4.02-3.93 (m, 1H), 3.78-
3.70 (m, 1H), 3.51-3.44 (m, 1H), 3.29 (dd, J ) 13.6, 9.2, 1H),
3.13 (s, 3H), 3.08 (dd, J ) 13.6, 4.4, 1H), 2.46 (s, 3H), 2.33 (s,
3H), 1.00-0.90 (m, 21H). 13C NMR (100 MHz, CDCl3) δ 167.0,
150.1, 144.1, 143.5, 137.7, 136.5, 134.4, 133.2, 131.1, 129.1, 128.3,
127.5, 127.3, 126.9, 126.7, 126.3, 120.3, 116.6, 122.1, 100.7, 96.9,
79.1, 69.8, 55.0, 43.8, 29.6, 21.4, 17.8, 13.7, 12.8. IR (thin film) ν
2868, 1654, 1597, 1265, 1153, 1029 cm-1. HRMS calcd for
C44H56N2O7SSi: 783.3499. Found: 783.3506.
580 J. Org. Chem., Vol. 72, No. 2, 2007

Total Synthesis of the (()-CC-1065 CPI Subunit
5-Trifloxyindole Benzamide (29). To the indole amide 28 (0.625
g, 0.795 mmol) in 20 mL of dry THF was added 0.835 mL (8.35
mmol) of TBAF (1.0 M in THF), and the reaction was stirred for
30 min. The reaction mixture was then partitioned between saturated
aqueous sodium bicarbonate and diethyl ether and extracted, and
then the aqueous wash was re-extracted twice. The combined
organic phases were washed with brine, dried over MgSO4, and
concentrated to yield a residue. A 0.501 g amount of this residue
was dissolved in 5 mL of dry THF and was added via cannula to
KOtBu (0.117 g, 0.957 mmol) in 5 mL of dry THF at 0 °C and
stirred for 15 min before PhNTf2 (0.313 g, 0.876 mmol) in 5 mL
of dry THF was added via cannula. The reaction was allowed to
warm to room temperature, and after 30 min at this temperature,
the reaction mixture was quenched with 5% HCl and extracted
thrice with diethyl ether. The organic extracts were washed with
brine, dried over MgSO4, and concentrated to give a residue which
was purified by column chromatography (5-70% ethyl acetate:
hexanes gradient) to yield 0.562 g (93% yield over two steps) of
29 as a white foam: mp ) 68-70 °C. 1H NMR (400 MHz, CDCl3)
δ 7.84 (d, J ) 8.4, 2H), 7.72 (s, 1H), 7.53-7.42 (m, 5H), 7.39-
7.35 (m, 3H), 7.28-7.24 (m, 2H), 7.11 (d, J ) 8.4, 2H), 6.56 (s,
1H), 4.98 (s, 2H), 4.52 (d, J ) 6.8, 1H), 4.25 (d, J ) 6.8, 1H),
3.97-3.91 (m, 1H), 3.81 (ddd, J ) 14.0, 6.0, 3.6, 1H), 3.55-3.49
(m, 1H), 3.38 (dd, J ) 14.4, 9.6, 1H), 3.18 (dd, J ) 14.4, J ) 4.4,
1H), 3.09 (s, 3H), 2.50 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 167.4, 145.2, 144.2 (2C), 137.0, 135.2, 134.3, 132.6,
131.4, 129.4, 128.9, 128.5 (2C), 128.4, 128.0, 127.0, 126.9, 116.6,
116.3, 101.5, 96.5, 78.7, 71.1, 55.4, 43.3, 29.4, 21.5, 13.4. IR (thin
film) ν 3341, 2942, 1650.3, 1536, 1217, 1140, 1074 cm-1. HRMS
calcd for C36H35F3N2O9S2: 760.1736. Found: 760.1750.
Pyrrolo[3,2-f]tetrahydroquinoline (30). To the aryl trifloxy
cross-coupling partner 29 (0.430 g, 0.566 mmol) was added 12.0
mL of dry dioxane. The resulting solution was stirred with argon
purging for 30 min at room temperature to remove any dissolved
gases in the solvent/aryl trifloxy substrate. Meanwhile, to a Schlenk
tube, which had been previously purged and back-filled with argon
three times, was added Cs2CO3 (0.258 g, 0.792 mmol), Pd2(dba)3
(0.052 g, 0.057 mmol), and Xantphos (0.098 g, 0.170 mmol). After
addition of these solid reagents the Schlenk tube was again purged
and back-filled with argon three times before exchanging a screw
cap for a septum and adding the aryl trifloxy substrate in dioxane
by cannula to the Schlenk tube. The septum was then quickly
exchanged for a screw cap, the Schlenk tube was then placed in a
sand bath, and the reaction was allowed to occur over 18 h, at which
time the Schlenk tube was charged with a further Pd2(dba)3 (0.026
g, 0.027 mmol) and the reaction continued for a further 20 h. After
this time 10 mL of 5% HCl was added, and the aqueous phase was
then washed three times with diethyl ether. The organic extracts
were then washed with brine and dried over MgSO4 before being
concentrated with SiO2 in vacuo to yield solid supported adduct,
which was then subjected to column chromatography (5-45%
gradient of ethyl acetate in hexanes) to yield 0.378 g (88%) of
pyrrolo[3,2-f] tetrahydroquinoline 30 as a white semisolid. 1H NMR
(600 MHz, CDCl3) δ 7.57 (s, 1H), 7.38 (d, J ) 9.0, 2H), 7.35-
7.22 (m, 8H), 7.01 (d, J ) 9.0, 4H), 5.97 (br s, 1H), 4.74 (d, J )
4.8, 1H), 4.68 (d, J ) 4.8, 1H), 4.42-4.16 (m, 4H), 3.77 (dd, J )
12.6, 3.0, 1H), 3.49 (dd, J ) 16.8, 5.7, 1H), 3.36 (s, 3H), 3.33 (dd,
J ) 17.4, 4.8, 1H), 2.48 (s, 3H), 2.32 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 143.9, 143.6, 137.2, 136.4, 136.2, 131.6, 129.9, 129.1,
128.5, 128.3, 128.1, 127.8, 127.3, 127.2, 126.9, 123.0, 116.4, 113.2,
94.9, 70.9, 69.7, 55.6, 31.2, 21.4, 13.5. IR (thin film) ν 2927, 1653,
1362, 1168, 1095, 1040 cm-1. HRMS calcd for C35H34N2O6S:
610.2138. Found: 610.2138.
washed with brine, and dried over MgSO4 before being concentrated
to yield 0.228 g of debenzylated secondary alcohol. In 5.0 mL of
dry THF containing 0.100 g (0.298 mmol) of this compound was
added diisopropylazodicarboxylate (0.041 mL, 0.298 mmol), fol-
lowed by triphenylphosphine (0.055 g, 0.298 mmol) at room
temperature. After 15 min the reaction mixture was concentrated
with SiO2 to leave a silica-supported crude product. The crude
mixture was purified by flash chromatography (1-3% acetone in
1
DCM) to yield 0.0851 g (89% yield) of white semisolid 32. H
NMR (600 MHz, CDCl3) δ 7.88 (d, J ) 8.4, 2H), 7.54 (s, 1H),
7.47-7.44 (m, 3H), 7.35 (t, J ) 7.8, 2H), 7.25 (d, J ) 7.8, 2H),
5.42 (s, 1H), 4.12-4.07 (m, 2H), 2.93 (ddd., J ) 12.0, 6.0, 4.8,
1H), 2.36 (s, 3H), 2.08 (dd, J ) 7.2, 4.8, 1H), 2.03 (s, 3H), 1.50 (t,
J ) 4.8). 13C NMR (100 MHz, CDCl3) δ 174.4, 169.6, 158.2, 144.6,
135.7, 134.8, 134.2, 131.9, 129.1, 128.7, 128.5, 127.8, 127.3, 115.5,
112.7, 53.4, 32.2, 21.9, 21.6, 21.5, 9.9. IR (thin film) ν 2959, 1722,
1631, 1390, 1246, 1106 cm-1. HRMS calcd for C26H22N2O4S:
458.1300. Found: 458.1286.
1,2,8,8′-Tetrahydrocyclopropa[c]indol-4-one (CPI-33). The
tosylated pyrrole 32 (0.045 g, 0.10 mmol) was dissolved in 1.0
mL of 1 N NaOMe at 0 °C and stirred overnight, after which time
the reaction mixture was worked up with 2.5 mL of 10% aqueous
Na2HPO4 and extracted seven times with DCM. The organic phase
was washed with brine and triethylamine, and silica was added to
it before concentration to leave solid-supported crude 33. A column
was equilibrated with 5% triethylamine/1:1 THF:ethyl acetate, and
the supported product was flashed with this eluent to give 0.014 g
1
(74% yield) of the white semisolid CC-1065 CPI (33). H NMR
(600 MHz, CDCl3) δ 9.23 (br s, 1H), 6.70 (d, J ) 1.8, 1H), 5.51
(s, 1H), 4.66 (br s, 1H), 3.78 (ddd, J ) 9.6, 5.4, 1.8, 1H), 3.62 (d,
J ) 9.6, 1H), 2.95 (m, 1H), 1.99 (s, 3H), 1.85 (dd, J ) 7.8, 4.2,
1H), 1.20, (t, J ) 4.2, 1H). 13C NMR (125 MHz, CDCl3) δ 177.7,
120.8, 113.6, 96.0, 51.0, 23.1, 22.7, 14.1, 10.0. IR (thin film) ν
3462, 1611 cm-1. HRMS calcd for C12H12N2O: 200.0950. Found:
200.0959.
Note: All data giVen aboVe are in agreement with the literature
Values.5a
N-Methylindole-2-carboxamide-Linked Indole (35). To the
cyanoindole 24 (0.500, 0.738 mmol) in 10 mL of dry diethyl ether
was added powdered lithium aluminum hydride (LAH) (0.112 g,
2.95 mmol) portion-wise at 0 °C. After completion of the addition
of LAH, the reaction mixture was warmed to room temperature,
and after 20 min, 1 N NaOH was added dropwise until a white
precipitate formed. The reaction mixture was then filtered over celite
and concentrated to yield a residue which was immediately taken
up in 5 mL of dry dioxane. To this solution was added triethylamine
(0.207 mL, 1.48 mmol), followed by catalytic DMAP, and finally
N-methylindole-2-carbonyl chloride 34 (0.131 g, 0.724 mmol).9 This
reaction mixture was stirred for 22 h, at which point the mixture
was extracted twice with diethyl ether; the organic extracts were
washed with brine, dried over MgSO4, and concentrated to yield a
residue. The residue was purified by flash chromatography (2-
20% ethyl acetate:hexanes gradient) to yield 0.555 g (91% yield
1
over two steps) of the white semisolid (35). H NMR (400 MHz,
CDCl3) δ 7.88 (d, J ) 8.4, 2H), 7.58 (d, J ) 12.8, H), 7.36 (d, J
) 8.4, 1H), 7.35-7.26 (m, 5H), 7.16-7.09 (m, 5H), 7.03 (t, J )
4.8, 1H), 6.77 (s, 1H), 4.95-4.82 (AB, δA ) 4.93, δB ) 4.84, JAB
) 13.6, 2H), 4.45 (d, J ) 6.4, 1H), 4.23 (d, J ) 6.4, 1H), 4.01 (s,
3H), 4.01-3.94 (m, 1H), 3.69 (ddd, J ) 14.0, 6.0, 4.2, 1H), 3.46
(ddd, J ) 13.6, 7.6, 4.2, 1H), 3.30 (dd, J ) 14.4, 8.8, 1H), 3.20 (s,
3H), 3.07 (dd, J ) 13.2, 5.2, 1H), 2.48 (s, 3H), 1.09-0.88 (m,
21H). 13C NMR (100 MHz, CDCl3) δ 162.3, 150.1, 144.2, 143.5,
138.7, 137.7, 136.6, 133.2, 132.1, 129.1, 128.3, 127.5, 127.3, 126.9,
126.3, 125.9, 123.7, 121.6, 120.3, 120.2, 116.6, 112.2, 109.9, 103.3,
100.8, 96.8, 78.8, 69.8, 55.2, 43.4, 31.3, 29.7, 21.4, 17.8, 13.8, 12.8.
IR (thin film) ν 3375, 2945, 1662, 1533, 1490, 1394, 1153, 1029
cm-1. HRMS calcd for C47H59N3O7SSi: 837.3843. Found: 837.3834.
N-Methylindole-2-carboxamide-Linked 5-Trifloxyindole (36).
To the indole amide 35 (0.497 g, 0.590 mmol) of in 20 mL of dry
Protected CC-1065 CPI Subunit (32). To the pyrrolo[3,2-f]-
tetrahydroquinoline 30 (0.500 g, 0.883 mmol) in 25 mL of dry DCM
at -78 °C was added BCl3 (2.65 mL, 2.65 mmol), and after 15
min the reaction mixture was quenched with saturated sodium
bicarbonate. After warming to room temperature the phases were
separated and the aqueous phase was re-extracted thrice with DCM,
J. Org. Chem, Vol. 72, No. 2, 2007 581

Ganton and Kerr
THF was added 0.651 mL (0.651 mmol) of TBAF (1.0 M in THF),
and the reaction was stirred for 30 min. The reaction mixture was
then partitioned between saturated aqueous sodium bicarbonate and
diethyl ether and extracted, and then the aqueous wash was re-
extracted twice. The combined organic phases were washed with
brine, dried over MgSO4, and concentrated to yield a residue. This
residue was dissolved in 5 mL of dry THF and added via cannula
to a solution of KOtBu (0.104 g, 0.853 mmol) in 5 mL of dry THF
at 0 °C. This mixture was stirred for 15 min before PhNTf2 (0.307
g, 0.860 mmol) in 5 mL of dry THF was added via cannula. The
reaction was allowed to warm to room temperature, and after 30
min at this temperature, the reaction mixture was quenched with
5% HCl and extracted thrice with diethyl ether. The organic extracts
were washed with brine, dried over MgSO4, and concentrated to
give a residue which was purified by column chromatography (2-
30% ethyl acetate:hexanes gradient) to yield 0.414 g (93% yield
Schlenk tube. The septum was then quickly exchanged for a screw
cap, the Schlenk tube was then placed in a sand bath, and the
reaction was allowed to occur over 22 h, at which time 10 mL of
5% HCl was added and the aqueous phase was then washed three
times with diethyl ether. The organic extracts were then washed
with brine and dried over MgSO4 before being concentrated with
SiO2 in vacuo to yield solid-supported adduct which was then
subjected to column chromatography (5-55% gradient of ethyl
acetate in hexanes) to yield 0.176 g (61% yield) of pyrrolo[3,2-f]-
1
tetrahydroquinoline 37 as a white semisolid. H NMR (400 MHz,
CDCl3) δ 7.58 (d, J ) 0.8, 2H), 7.53 (d, J ) 8.0, 1H), 7.35 (dt,
J ) 8.4, 2.0, 2H), 7.31-7.26 (m, 1H), 7.24-7.16 (m, 4H), 7.12
(dt, J ) 8.0, 0.8, 1H), 7.01 (d, J ) 8.4, 2H), 6.85 (d, J ) 6.4, 2H),
6.52 (s, 1H), 6.12 (br s, 1H), 4.73-4.64 (AB, δA ) 4.72, δB
)
4.68, JAB ) 6.8, 2H), 4.43 (dd, J ) 12.8, 4.8, 1H), 4.31-4.36 (m,
1H), 4.21 (br s, 2H), 3.73 (dd, J ) 13.2, 2.8 1H), 3.57 (s, 3H),
3.47 (d, J ) 5.6, 1H), 3.38 (d, J ) 2.8, 1H), 3.34 (s, 3H), 2.49 (s,
3H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.9, 144.2,
143.6, 137.8, 137.1, 136.2, 133.8, 132.9, 131.5, 129.2, 128.1, 127.7,
127.2, 127.0, 126.9, 126.4, 123.5, 123.2, 121.8, 120.2, 116.4, 113.3,
109.8, 106.0, 105.6, 94.8, 70.7, 69.3, 55.6, 31.0, 30.9, 21.5, 13.6.
IR (thin film) ν 2928, 1654, 1636, 1457 cm-1. HRMS calcd for
C38H37N3O6S: 663.2403. Found: 663.2397.
1
over two steps) of white foam 36. H NMR (400 MHz, CDCl3) δ
7.72 (d, J ) 1.2, 1H), 7.65 (d, J ) 8.0, 1H), 7.47 (d, J ) 8.4, 1H),
7.40-7.30 (m, 5H), 7.26-7.23 (m, 2H), 7.15 (td, J ) 8.0,1.2, 1H),
7.10 (d, J ) 8.4, 3H), 6.93 (s, 1H), 6.56 (s, 1H), 4.97 (s, 2H), 4.53
(d, J ) 6.8, 1H), 4.28 (d, J ) 6.8, 1H), 4.07 (s, 3H), 3.98-3.92
(m, 1H), 3.77 (ddd, J ) 14.0, 6.4, 3.6, 1H), 3.51 (ddd, J ) 14.0,
6.4, 4.8, 1H), 3.39 (dd, J ) 14.4, 9.6, 1H), 3.18 (dd, J ) 14.4, 4.4,
1H), 3.12 (s, 3H), 2.51 (s, 3H), 2.36 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 162.7, 145.1, 144.1, 139.0, 137.0, 135.2, 132.6, 131.8,
129.4, 128.9, 128.5, 128.4, 127.9, 127.0, 126.0, 124.4, 123.9, 121.8,
120.3, 116.5, 116.2, 110.1, 103.9, 101.5, 96.5, 78.6, 71.1, 55.4,
42.8, 31.5, 29.5, 21.5, 13.5. IR (thin film) ν 3406, 2936, 1654,
1540, 1420, 1220, 1140 cm-1. HRMS calcd for C40H42F3N3O9S2:
813.2002. Found: 813.2013.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada (NSERC), Med-
mira Laboratories, Inc., the Ontario Ministry of Science and
Technology, and GlaxoSmithKline for funding. We thank the
donors of the American Chemical Society Petroleum Research
Fund for partial support of this research. M.D.G. is a recipient
of NSERC PGSA, PGSD, and OGSST scholarships. We thank
Mr. Doug Hairsine of the UWO Mass Spectrometry Facility
for performing MS analysis.
N-Methylindole-2-carboxamide-N′-pyrrolo[3,2-f]tetrahydro-
quinoline (37). To the aryl trifloxy cross-coupling partner 36 (0.353
g, 0.566 mmol) was added 6.0 mL of dry dioxane. The resulting
solution was stirred with argon purging for 30 min at room
temperature to remove any dissolved gases in the solvent/aryl
trifloxy substrate. Meanwhile, to a Schlenk tube, which had been
previously purged and back-filled with argon three times, was added
Cs2CO3 (0.277 g, 0.849 mmol), Pd2(dba)3 (0.040 g, 0.043 mmol),
and Xantphos (0.075 g, 0.130 mmol). After addition of these solid
reagents, the Schlenk tube was again purged and back-filled with
argon three times before exchanging a screw cap for a septum and
adding the aryl trifloxy substrate in dioxane by cannula to the
Supporting Information Available: Experimental details for
the preparation of compounds 12, 13, 14a, 14b, 16a, 16b, 17a,
1
17b, 18a, 18b, and 26; spectroscopic data in the form of H and
13C NMR for all compounds, except 22 and 31. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO062064J
582 J. Org. Chem., Vol. 72, No. 2, 2007