Novel cycloalkene indole carbazole alkaloids via the ring closing metathesis reaction

Article abstract of DOI:10.1016/j.tetlet.2007.08.006

Methodology for the synthesis of a series of carbocyclic indole carbazole natural product analogs is presented. The chemistry involves construction of the core indole, followed by attachment of double bond tethered side chains of three and four carbon len

Full text of DOI:10.1016/j.tetlet.2007.08.006

Tetrahedron Letters 48 (2007) 7399–7403
Novel cycloalkene indole carbazole alkaloids via the ring
closing metathesis reaction
Lawrence J. Wilson,* Cangming Yang and William V. Murray
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 920 Route 202, PO Box 300, Raritan, NJ 08869, United States
Received 7 May 2007; revised 29 July 2007; accepted 1 August 2007
Available online 6 August 2007
Abstract—Methodology for the synthesis of a series of carbocyclic indole carbazole natural product analogs is presented. The chem-
istry involves construction of the core indole, followed by attachment of double bond tethered side chains of three and four carbon
lengths. The bottom carbocyclic ring system is formed through a ring closing metathesis reaction, and allows the installation of four,
five, and six member ring sizes.
Ó 2007 Elsevier Ltd. All rights reserved.
The family of indole carbazole based natural products
have been the focus of much attention primarily due
to their diverse biological properties and are known to
act at specific biological targets such as protein kinases
and DNA topoisomerases.1 In fact, both staurosporine
and K-252a (Fig. 1) are broad spectrum protein kinase
inhibitors and many of their derivatives have been found
to selectively inhibit both serine/threonine and tyrosine
protein kinase family members.2 Furthermore, small
modifications on these scaffolds can have dramatic
effects on target specificity. In fact, synthetic and medic-
inal chemistry studies have provided many types of
semi-synthetic derivatives, which some have progressed
through various stages of human clinical testing
(Fig. 1, UCN-01, PKC412, CEP-701, and 1347)3 while
also being utilized to map ATP binding sites of protein
kinases through X-ray studies.4 Natural product mimet-
ics have the advantage of a high chance of target direc-
ted effects and have been estimated to be the basis for up
to 40–75% of new drugs in the past few decades.5
For these reasons, we initiated a drug discovery effort
around this natural product scaffold for the purpose of
creating novel protein kinase inhibitors.3 Although these
natural products are isolated by fermentation, the mate-
rials are quite costly and not readily accessible. Several
novel and divergent approaches have been developed
for the synthesis of the indole carbazole natural prod-
ucts as well as the core aglycons. These include the total
synthesis of staurosporine and K-252a,6 synthesis of the
bis-indole maleimide acryflavins and acryrubins,7,8
numerous synthesis of the aglycon K-252c (3d),6b,9
various chemistries on the indole nitrogens,10 organo-
metallic ruthenium complexes,11 and olefin metathesis
constructing K-252a dimers.12
H
N
H
N
H
N
X
X
O
O
O
X
X
Our approach was to provide a design that would allow
compounds to be assembled quickly and efficiently,
while keeping most of the molecular structural features
of the natural products intact (1, Fig. 1, Scheme 1).
Removing the methyl substituent and oxygen on the
sugar ring provides a much simpler product to be con-
structed by a modular combination coupling alkylation
and ring closing metathesis chemistries on bis-indole
precursors. The olefin metathesis reaction resulting in
ring formation (ring closing metathesis or RCM) has
become an important and powerful reaction within the
field of synthetic organic chemistry.13 The ruthenium
N
N
N
N
N
N
O
O
n
HO
m
Y
Z
MeO
R
NMe(R)
K-252a (X=H, R=CO2Me)
CEP-701 (X=H, R=CH2OH)
CEP-1347 (X=CH2SEt,
R=CO2Me)
1
Staurosporine (R=X=H)
UCN-01 (X=OH, R=H)
PKC412 (X=H, R=COPh)
Figure 1. Selected indole carbazole natural products and analogs.
*
Corresponding author. Tel.: +1 404 727 3277; fax: +1 404
7274506; e-mail: wilsonlarr@gmail.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.006

7400
L. J. Wilson et al. / Tetrahedron Letters 48 (2007) 7399–7403
Y
Our route was initiated by construction of the indole
O
carbazole core molecules, which would later be sub-
jected to the double alkylation and ring closing metathe-
sis reactions. Following a blend of known approaches,
both mono and di-carbonyl versions of the indole car-
bazoles were constructed (Scheme 1, 3a–d). The malei-
mide compounds (3a and 3b) were synthesized from
dichloromaleic anhydride according to or through adap-
tations of existing procedures through the various
non-bridged compounds (2a and 2b).7,8 In the case of
the 2,4-dimethoxybenzyl derivative (3b), tuning oxida-
tion conditions were necessary to avoid loss of the benz-
yl protecting group. The natural product K-252c (3d)
has been synthesized by many different routes. We
selected the following route: (i) condensation of (1H-in-
dol-3-yl)-oxo-acetic acid methyl ester and 2-(1H-indol-3-
yl)-acetamide to give acryrubin A (2c);7 (ii) oxidation
with palladium chloride to give acryflavin A (3c, 80%);
Clemmenson reduction with tin metal in the presence
of hydrochloric acid to give the natural product K-
252c (3d, 86%).9
X
R
N
O
O
N
H
b
a
c or d
(X=O, Y=OMe)
(X=CH2, Y=NH2)
N
H
N
H
O
O
O
2a (R=Me)
2b (R=2,4-(MeO)2PhCH2)
2c (R=H)
Cl
Cl
R
N
R
N
X
O
X
O
f - l
(see Table 1)
N
N
N
H
N
H
Ra
Rb
n
m
3a (R=Me, X=O)
3b (R=2,4-(MeO)2PhCH2, X=O)
4a, 4b (R=Me, X=O)
4c (R=2,4-(MeO)2PhCH2, X=O)
4d, 4f, 4h (R=H, X=H2)
3c (R=H, X=O)
e
3d (R=H, X=H2)
4e, 4g, 4i (R=Boc, X=H2)
R
N
O
Table 1. Yields and structures of bis-alkene precursors
X
n
Entry
Step(s)/yields (%)
Product (4a–h)
I or II
Me
N
Solvent
N
N
O
O
Temperature
(see Table 2)
m
Ra
Rb
5a,5b (R=Me, X=O)
5c (R=2,4-(MeO)2PhCH2, X=O)
5d, 5g (R=H, X=H2)
N
N
n
5e, 5f, 5h (R=Boc, X=H2)
1
2
f/83
g/55, f/99
4a (n = 1)
4b (n = 2)
Scheme 1. Synthesis of indole carbazole alkene derivatives. Reagents
and conditions: 2a see Ref. 8; 2c see Ref. 7; (a) AcOH, 80 °C, 18 h, 2,4-
(MeO)2PhCH2NH2, (87% ); (b) indole, EtMgBr, Et2O, THF, reflux,
24 h, (56% fpr 2b); (c) DDQ, p-TsOH (cat.), PhCH3, 1,4-dioxane
(100% for 3b); (d) PdCl2, DMF, 90 °C (for 2c to 3c, 80%); (e) Sn0, HCl,
AcOH 100 °C (96%); (f) Cs2CO3, allyl bromide, DMF, rt; (g) Cs2CO3,
4-bromo-1-butene, DMSO, rt; (h) methallyl chloride, Cs2CO3, DMF;
(i) NaH, THF, allyl bromide, À50 °C to rt; (j) Cs2CO3, methyl-(2-
bromomethyl)-acrylate, DMF, rt; (k) 4-bromo-1-butene, Cs2CO3,
CH3CN, lwave, 150 °C, 45 min; (l) Boc2O, DMAP, THF, MTBD.
MeO
MeO
O
N
O
3
i/51, j/96
N
N
O
CO2Me
4c
R
N
N
N
Mes
Mes
PCy3
Cl
Cl
Cl
Ph
H
Ph
H
Ru
Ru
Cl
PCy3
PCy3
N
N
Ra
Ra
I
II
Figure 2. Ruthenium based olefin metathesis catalysts used in this
study.
4
5
6
f/72
l/83
h/56, l/97
4d (R = H, Ra = H)
4e (R = BOC, Ra = H)
4f (R = BOC; Ra = Me)
catalysts developed by Grubbs (Fig. 2, I and II)14 have
been utilized for RCM based ring formation as a key
step in several nitrogen heterocycle based natural prod-
uct synthesis.14,15 The ring closing reaction would allow
more flexibility in the design and execution of this
process. Also, this tandem methodology would provide
novel derivatives with a deoxy sugar ring, while the
double bond would be an isosteric sugar replacement
and also allow for further manipulations.
R
N
O
N
N
7
8
k/40
l/91
4g (R = H)
4h (R = BOC)

L. J. Wilson et al. / Tetrahedron Letters 48 (2007) 7399–7403
7401
The first part of our strategy after construction of the
bis-indole nucleus was to alkylate the two indole nitro-
gens, in both symmetrical and differential directions
with either three and four carbon (Table 1) alkenyl
chains. N-methyl acryflavin derivative (3a) could be
symmetrically allylated in high yield under standard
conditions with allyl bromide to give the bis-allyl deri-
vative (4a). Furthermore, a differential sequence could
be performed by reaction with 1-butenyl bromide using
sodium hydride as base, followed by allyl bromide
giving rise to the product with both three and four car-
bon lengths (4b).
at À50 °C and then reaction with allyl bromide in 51%
yield. Allylation was next carried out with bromo-pro-
penoate methyl ester under reaction with carbonate base
and provided a precursor to an analog with a double
bond carboxymethyl substituent (4c) in 96% yield. Fur-
thermore, it provides the appending functionality found
in the sugar portion of the natural product K-252a.
Our next goal was to alkylate the pyrrolidinone based
bis-indole natural product K-252c (3d). We found, in
the case of symmetrical di-alkylations, that we could
alkylate selectively without protecting the pyrrolidinone
nitrogen. Reaction with cesium carbonate as base and
allyl bromide, and methyl-propenyl chloride provided
the corresponding bis-allyl (4d) and bis-methallyl (4f)
derivatives in 72% and 56% yields. For the bis-homo-
allyl case (4g), microwave heating enabled efficient
Another variation of this concept was provided with
N-2,4-dimethoxybenzyl derivative (Table 1, 3b). Mono-
allylation could be conducted by alkylation at low tem-
perature in good yield by exposure with sodium hydride
Table 2. Yields and structures of olefin metathesis reactions
Entry
Catalyst/conditions
Product (5a–h)
Yield (%)
Me
N
O
O
N
N
n
1
2
I, DCM, rt, 6 h
I, DCM, rt, 1 h
5a (n = 1)
5b (n = 2)
85
96
MeO
MeO
O
N
O
3
II Cl(CH2)2Cl 150 °C, lwave, 5 min
64
N
N
CO2Me
5c
R
N
O
N
N
Ra
Ra
4
5
6
I, DCM, 40 °C, 40 h
I, DCM, rt, 20 h
II, PhCH3, 110 °C, 42 h
5d (R = Ra = H)
5e (R = Boc; Ra = H)
5f (R = Boc; Ra = Me)
55
85
51
R
N
O
N
N
7
8
I, DCM, rt, 5 days
I, DCM, 40 °C, 4 h
5g (R = H)
5h (R = Boc)
31
88

7402
L. J. Wilson et al. / Tetrahedron Letters 48 (2007) 7399–7403
bis-alkylation in 40% yield and surprisingly, no alkyl-
ation on the pyrrolidinone nitrogen was observed. After
reaction of the indole nitrogens, it was possible to pro-
tect the pyrrolidinone nitrogen with a t-butoxycarbonyl
group by treatment with t-butylcarbonyl anhydride and
7-methyl-1,5,7-triazabicyclo[4.4.0] dec-5-ene (MTBD) in
good to excellent yields (4e, f, h).
Acknowledgments
This is dedicated to all the discovery scientists that
worked at the J&J Raritan campus. The authors
acknowledge the contributions of the various chemistry
support groups at J&J, especially Amy Maden and Ken-
neth Wells.
We were ready to then execute the second part of our
strategy, the ring closing metathesis. First, we investi-
gated the acryflavin A derivatives (Table 2, 4a–c) and
treatment of N-methyl bis-allyl compound (4a) with
Grubb’s first generation ruthenium catalyst (I) in dichlo-
romethane at room temperature resulted in immediate
formation of the ring closed product (5a) in high yield
(85%). Next, the butenyl–allyl product (4b) was exposed
to the same conditions, and this resulted in rapid forma-
tion of the five carbon ring closed product (5b) in high
yield (96%). We then were interested in including more
complex functionality, and inclusion of a carboxymethyl
substituent would furnish functionality that was present
in the sugar portion of the natural product K-252a. We
had previously reported that this substituent could be
used in an heterocycle based RCM reaction under
microwave irradiation.16 Exposure of substrate (4c) to
those same conditions using the type II catalyst (II) pro-
ceeded in good yield (64%) to the corresponding unsat-
urated system (5c).
Supplementary data
Experimental data including procedures and spectral
data for all compounds is included in the supplementary
data. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2007.08.006.
References and notes
1. Sanchez, C.; Mendez, C.; Salas, J. A. Nat. Prod. Rep.
2006, 23, 1007.
2. (a) Omura, S.; Sasaki, Y.; Iwai, Y.; Takeshima, H. J.
Antibiot. 1995, 48, 535; (b) Ruggeri, B. A.; Miknyoczki, S.
J.; Shing, J.; Hudkins, R. L. Curr. Med. Chem. 1999, 6,
845.
3. (a) Mucke, H. A. M. Idrugs 2003, 6, 377; (b) Kaneko, M.;
Saito, Y.; Saito, H.; Matsumoto, T.; Matsuda, Y.; Vaught,
J. L.; Dionne, C. A.; Angeles, T. S.; Glicksman, M. A.;
Neff, N. T.; Rotella, D. P.; Kauer, J. C.; Mallamo, J. P.;
Hudkins, R. L.; Murakata, C. J. Med. Chem. 1997, 40,
1863; (c) Fabbro, D.; Ruetz, S.; Bodis, S.; Pruschy, K.;
Csermak, K.; Man, A.; Campochiaro, P.; Wood, J.;
Reilly, T. O.; Meyer, T. Anti-Cancer Drug Des. 2000, 15,
17; (d) Ruggeri, B. A.; Miknyoczki, S. J.; Singh, J.;
Hudkins, R. L. Curr. Med. Chem. 1999, 6, 845.
4. (a) Schlering, N.; Knapp, S.; Marconi, M.; Fiocco, M. M.;
Cui, J.; Perego, R.; Rusconi, L.; Cristiani, C. Proc. Natl.
Acad. Sci. 2003, 100, 12654; (b) Bartlett, S.; Beddard, G.
S.; Jackson, R. M.; Kayser, V.; Kilner, C.; Leach, A.;
Nelson, A.; Oledzki, P. R.; Parker, P.; Reid, G. D.;
Warriner, S. L. J. Am. Chem. Soc. 2005, 127, 11699.
5. Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod.
2003, 66, 1022.
6. (a) Link, J. T.; Raghavan, S.; Danishefsky, S. J. Stauro-
sporine. J. Am. Chem. Soc. 1995, 117, 552; (b) K-252a,
Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J.; Pflum, D. A.;
Petsch, D. T. J. Am. Chem. Soc. 1997, 119, 9641.
7. Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J. Org.
Chem. 1998, 63, 6053.
8. Slater, M. J.; Cockerill, S.; Baxter, R.; Bonser, R. W.;
Gohil, K.; Gowrie, C.; Robinson, J. E.; Littler, E.; Parry,
N.; Randall, R.; Snowden, W. Bioorg. Med. Chem. 1999,
7, 1067.
We next turned our attention to the pyrrolidinone deri-
vatives (Table 2, entries 4–8). Initially, we exposed the
unprotected bis-allyl substrate (4d) to conditions used
in the acryflavin derivative case. Reaction with Grubbs
type I catalyst (I) proceeded sluggishly. Although the
product (5d) was formed in 55% yield, it took several
days at reflux to reach completion. N-Boc derivative
(4e) proved to be more compatible, giving a higher yield
(5e, 85%) in shorter time. This is further evidence and
consistent with other observations in the RCM that
unprotected nitrogen groups slow the reaction. How-
ever, because the hydrogen on the pyrrolidinone nitro-
gen is needed for interaction with most protein
kinases, this represents only five linear steps to a fully
functional derivative (5d). The same observation was
made in the six carbon carbocycle case (4g and 4h),
showing an even lower yield (31%) in the unprotected
(5g) versus N-Boc case (5h, 88%). Finally, we show here
that it is possible to generate tetrasubstituted double
bonds in this procedure (5f, entry 6), albiet in a more
modest yield (51%). In this case, optimization of reac-
tion conditions show it was better to conduct the reac-
tion in refluxing toluene rather than utilizing the
microwave radiation conditions developed for the carb-
oxymethyl example (5c).
9. (a) Xie, G.; Lowe, J. W. Tetrahedron Lett. 1994, 35, 5555;
(b) Gaudencio, S. P.; Santos, M. M. M.; Lobo, A. M.;
Prabhakar, S. Tetrahedron Lett. 2003, 44, 2577; (c) Reddy,
G. M.; Chen, S.-Y.; Uang, B.-J. Synthesis 2003, 497.
10. (a) Kleinschroth, J.; Hartenstein, J.; Rudolph, C.; Schach-
tele, C. Bioorg. Med. Chem. Lett. 1993, 3, 1959; (b)
Tamaki, K.; Shotwell, J. B.; White, R. D.; Drutu, I.;
Petsch, D. T.; Nheu, T. V.; He, H.; Hirokawa, Y.; Maruta,
H.; Wood, J. L. Org. Lett. 2001, 3, 1689.
In summary, we have provided a general strategy for the
assembly of cycloalkene natural product derivatives.
This methodology produces compounds suitable to be
derivatized into protein kinase inhibitors. The applica-
tion of the RCM reaction provides a unique method
of closing the bottom ring and providing an isosteric
replacement of the sugar ring. Further reports on the
progress of these studies are forthcoming.
11. Zhang, L.; Carroll, P.; Meggers, E. Org. Lett. 2004, 6,
521.

L. J. Wilson et al. / Tetrahedron Letters 48 (2007) 7399–7403
7403
12. Tamaki, K.; Huntsman, E. W. D.; Petsch, D. T.; Wood, J.
L. Tetrahedron Lett. 2002, 43, 379.
14. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18.
13. (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem.
Soc. 1993, 115, 9856; (b) Miller, S. J.; Blackwell, H. E.;
Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9006; (c)
Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62,
7310; (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413.
15. (a) Martin, S. F. Pure Appl. Chem. 2005, 77, 1207; (b)
Arisawa, M.; Nishida, A.; Nakagawa, M. J. Organomet.
Chem. 2006, 691, 5109; (c) Deiters, A.; Martin, S. F.
Chem. Rev. 2004, 104, 2199.
16. Yang, C.; Murray, W. M.; Wilson, L. J. Tetrahedron Lett.
2003, 44, 1783.