Total synthesis of (±)-cis-trikentrin B via intermolecular 6,7-indole aryne cycloaddition and Stille cross-coupling

Article abstract of DOI:10.1016/j.tetlet.2012.11.125

An efficient total synthesis of the annulated indole natural product (±)-cis-trikentrin B was accomplished by means of a regioselectively generated 6,7-indole aryne cycloaddition via selective metal-halogen exchange from a 5,6,7-tribromoindole. The unaffected C-5 bromine was subsequently used for a Stille cross-coupling to install the butenyl side chain and complete the synthesis. This strategy provides rapid access into the trikentrins and the related herbindoles, and represents another application of this methodology to natural products total synthesis. The required 5,6,7-indole aryne precursor was prepared using the Leimgruber-Batcho indole synthesis.

Full text of DOI:10.1016/j.tetlet.2012.11.125

Tetrahedron Letters 54 (2013) 913–917
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of ( )-cis-trikentrin B via intermolecular 6,7-indole aryne
cycloaddition and Stille cross-coupling
Nalin Chandrasoma a, Neil Brown a,b, Allen Brassfield a, Alok Nerurkar a, Susana Suarez a,
Keith R. Buszek a,b,
⇑
a Department of Chemistry, University of Missouri, 205 Kenneth A. Spencer Chemical Laboratories, 5100 Rockhill Road, Kansas City, MO 64110, USA
b Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, Del Shankel Structural Biology Center, 2034 Becker Drive, Lawrence, KS 66047, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient total synthesis of the annulated indole natural product ( )-cis-trikentrin B was accomplished
by means of a regioselectively generated 6,7-indole aryne cycloaddition via selective metal–halogen
exchange from a 5,6,7-tribromoindole. The unaffected C-5 bromine was subsequently used for a Stille
cross-coupling to install the butenyl side chain and complete the synthesis. This strategy provides rapid
access into the trikentrins and the related herbindoles, and represents another application of this meth-
odology to natural products total synthesis. The required 5,6,7-indole aryne precursor was prepared
using the Leimgruber–Batcho indole synthesis.
Received 25 October 2012
Accepted 27 November 2012
Available online 5 December 2012
This Letter is warmly dedicated to Professor
Michael E. Jung on the occasion of his 65th
birthday.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Aryne
Benzofuran
Trikentrin
Herbindole
Natural products
Cycloaddition
Total synthesis
Stille
Cross-coupling
The family of trikentrins1,2 and herbindoles3 are the most prom-
inent representatives of an uncommon class of indole alkaloid nat-
ural products in which annulation is present around the benzene
nucleus (Fig. 1). Other architecturally complex members of this
type include the teleocidins,4 the penitrims,5 and the nodulisporic
acids.6
same o-silyl triflates8a which were used for other indole aryne
studies.8b–e
These biologically active compounds are fascinating structures
and they present remarkable synthetic challenges. The trikentrins
and the structurally related herbindoles in particular have been
the subject of numerous synthetic efforts over the years. The diffi-
culty in their construction is evident by many different creative ap-
proaches that have emerged from several laboratories.1,3
We recently were the first to generate the indole and benzo-
furan arynes associated with the benzene side of their respective
systems7 and reported a general method for their generation via
metal–halogen exchange (Scheme 1), and later from o-silyl tri-
flates.7b Garg subsequently reported a different route to the
N
H
N
H
N
H
N
H
cis-trikentrin A
trans-trikentrin A cis-trikentrin B
trans-trikentrin B
N
H
N
H
N
H
N
H
iso-trans-trikentrin B
herbindole A
herbindole B
herbindole C
⇑
Corresponding author. Tel.: +1 816 235 2292; fax: +1 816 235 5502.
E-mail address: buszekk@umkc.edu (K.R. Buszek).
Figure 1. The trikentrin and herbindole natural products.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.125

914
N. Chandrasoma et al. / Tetrahedron Letters 54 (2013) 913–917
Br
We applied our methodology to the total synthesis of ( )-cis-tri-
Br
Ph
Ph
Ph
kentrin A using a novel indole aryne cycloaddition as the key step
for installing the annulation at the 6,7-position of the benzene ring
(Scheme 2).9 In this first-generation synthesis,9a the 6,7-indole ar-
yne was generated from the corresponding N-tert-butyldimethylsi-
lyl-6,7-dibromo-4-ethylindole 11 (prepared from 9 using the
Bartoli indole synthesis10) via metal–halogen exchange and elimi-
nation, followed by cycloaddition with cyclopentadiene. Oxidative
cleavage of the olefin bridge in 12, bisdithioacetylization, and Ra-
ney nickel reduction gave the desired final target.
n-BuLi (2.2 equiv)
Et2O, -78 °C to rt
O
Ph
N
Me
1
(20 equiv)
N
Me
O
88%
2
Br
Br
Ph
n-BuLi (2.2 equiv)
Et2O, -78 °C to rt
O
N
N
Me
Me
3
4
(20 equiv)
In a subsequent second-generation effort involving the 4,6,7-
tribromoindole 16,9b we found that selective metal–halogen ex-
change occurred at the C-7 bromine in 17 (Scheme 3).
O
86%
Ph
n-BuLi (2.2 equiv)
Et2O, -78 °C to rt
This observation made it possible to effect the generation of the
6,7-indole aryne while retaining the C-4 bromine thus making it
available for later transition-metal cross-coupling chemistry (reac-
tion orthogonality). Indeed, the Negishi reaction with 18 was used
in this case to introduce the required ethyl group that afforded the
same late-stage intermediate 12 as was obtained in the first ap-
proach. We recently used this same tactic for the preparation of
novel annulated polycyclic indole libraries using Pd(0)-catalyzed
Br
N
N
Me
Me
O
Br
5
(20 equiv)
6
O
79%
Scheme 1. Indole arynes via metal–halogen exchange and their cycloadditions
with furan.
CH2=CHMgBr
CuBr2 (cat)
i) Ac2O
THF, -40 °C
52%
(Bartoli)
ii) HNO3
Br2
NO2
Br
NO2
iii) NaOH
NH2
t-BuONO
Br
NH2
7
ClCH2CH2Cl
H2O
MeCN
50 °C
82%
8
9
50-80 °C
96%
KHMDS
TBSOTf
THF, -78 °C
73%
n-BuLi, PhMe
Br
N
N
Br
N
H
10
TBS
TBS
-78 °C, rt
77%
Br
Br
11
12
( )-cis-Trikentrin A
N
H
Scheme 2. First-generation ( )-cis-trikentrin A synthesis.
Br
Br
Br2
CuBr2
t-BuONO
MeCN, 60 °C, 1 h
90%
CH2Cl2/MeOH (2:1)
NO2
Br
NO2
Br
Br
Br
NO2
rt, 1 h
99%
NH2
NH2
13
15
14
Br
NaH, TBSOTf, Et3N
CH2=CHMgBr (6.0 equiv)
DMF, 0 °C, 0.5 h
76%
-40 °C, THF
50%
Br
N
Br
N
TBS
Br
H
Br
17
16
Br
Et
n-BuLi (2.0 equiv)
(20 equiv)
Et2Zn (2.2 equiv)
Pd2(dba)3 (0.04 equiv)
P(t-Bu)3•HBF4 (0.16 equiv)
N
N
TBS
TBS
PhMe, -78 °C to rt
89%
THF, 65 °C, 1 h
70%
18
12
Scheme 3. Second-generation ( )-cis-trikentrin A synthesis.

N. Chandrasoma et al. / Tetrahedron Letters 54 (2013) 913–917
915
Br
Br
CuBr2 (1.3 equiv)
HBr (3.0 equiv)
N
H
N
H
19
N
H2O2 (2.0 equiv)
t-BuONO (1.6 equiv)
MeCN, 60 °C, 1 h
80%
TBS
Br
Br
Br
Br
MeOH, rt, 12 h
20
NH2
NH2
Br
28
( )-cis-Trikentrin B
Br
99%
26
27
NO2
Fuming HNO3 ( 2.0 equiv)
105 °C, 15 torr, 3 h
Br
N
1,2-dichloroethane, 0 °C, 1 h
82%
Br
Br
TBS
Br
30
CH
N
Br
29
21
(1.5 equiv)
3
Scheme 4. Retrosynthetic analysis of cis-trikentrin B.
N
Br
NH2NH2•H2O (3.95 equiv)
31
Suzuki–Miyaura
reactions.11
and
Buchwald–Hartwig
cross-coupling
NO2
activated carbon (3.3 equiv)
FeCl3•6H2O (0.065 equiv)
MeOH, 60 °C, 1 h
Br
Br
N
H
25
With the success of the second-generation synthesis of ( )-cis-
trikentrin A, it occurred to us that an analogous approach might
be possible for the total synthesis of ( )-cis-trikentrin B, which fea-
tures a butenyl side-chain at the C-5 position and which could be
installed via Stille cross-coupling with the ArBr 19 at C-5 (Scheme
4).
The key question centered on the intriguing issue of again
achieving selective metal–halogen exchange at C-7 but in the
5,6,7-tribromo indole system 21. We are delighted to report that
this is the case, and we now present the total synthesis of ( )-cis-
trikentrin B.
The first objective involved the synthesis of the 5,6,7-tribromo-
indole system 25. We envisioned a strategy that paralleled the suc-
cessful synthesis of 4,6,7-tribromoindole using the Bartoli indole
synthesis10 (Scheme 5). Thus, commercially available 2,6-dibromo-
aniline 22 was diazotized and brominated with CuBr2 to give 1,2,3-
tribromobenzene 2312 in 80% yield.
Nitration was achieved with fuming nitric acid to afford exclu-
sively 2,3,4-tribromonitrobenzene 2413 in 82% yield. Unfortu-
nately, application of the Bartoli indole synthesis (CH2@CHMgBr,
3.0 equiv, À40 °C) afforded the desired 5,6,7-tribromoindole in
only 32% yield. Silylation (NaH, 4.0 equiv; Et3N, 2.0 equiv; TBSOTf,
3.0 equiv) then produced the desired indole aryne precursor 21.
In an effort to increase the yield of 25, we examined other
potentially attractive approaches to the indole. The Leimgruber–
Batcho indole synthesis14 seemed especially suited to our needs
due to its combination of generally high yields and scalable
reactions.
Br
Br
Br
61% (2 steps)
Scheme 6. Synthesis of 5,6,7-tribromoindole via Leimgruber–Batcho route.
at 60 °C consistently afforded the desired 5,6,7-tribromoindole 25
in 61% yield in two steps from 29. Protection as its N-TBS ether
was accomplished as described above (78%).
Gratifyingly, the reaction of 21 with n-BuLi (2.0 equiv) at À78 °C
in toluene with an excess of cyclopentadiene and then warming
the mixture to room temperature over a period of 1 h gave the de-
sired cycloadduct 20 in 72% yield (Scheme 7).
We have also established that quenching the mixture at À78 °C
with water affords exclusively the N-TBS-5,6-dibromoindole 32,
thus confirming that the metal–halogen exchange is occurring only
at the C-7 bromo position. No other protonated compounds were
detected by this method. The basis for this selectivity is subject
of continuing investigations.
With the key cycloadduct in hand, we turned our attention to the
installation of the 6,7-annulated 1,3-cis-dimethyl cyclopentane
ring. The initital effort paralleled that of the ( )-cis-trikentrin A ef-
fort (Scheme 8). However, numerous attempts to hydrogenolyze
selectively the C–S bonds in 35 in the presence of the Ar–Br under
various conditions gave the desired indole 19 in only 16–31% yield,
with the remainder consisting mainly of the fully reduced indole 36.
A recent ( )-cis-trikentrin B total synthesis by Kerr and co-
workers3 used the Fujimoto reduction15 which we adapted for
Thus, inexpensive p-toluidine 26 was subjected to in situ bro-
mination (HBr, 3.0 equiv; H2O2, 2.0 equiv) in methanol to afford
quantitatively 2,6-dibromotoluidine, followed by diazotization as
described above to yield in 80% 3,4,5-tribromotoluene 28 (Scheme
6). Nitration was again achieved in 82% yield with fuming nitric
acid on a 14 g scale. Reaction of 29 with tripiperidinylmethane at
105 °C under vacuum for 3 h gave the enamine intermediate 31,
which was used immediately and without isolation for the next
step. FeCl3-catalyzed reaction with hydrazine hydrate in methanol
Br
Br
Br
Br
n-BuLi ( 2.0 equiv)
(20 equiv)
Br
N
N
N
TBS
TBS
TBS
Br
H
21
PhMe, -78 °C to rt
72%
20
32
Scheme 7. Regioselective C-7 metal–halogen exchange.
CuBr2 (1.3 equiv)
Fuming HNO3 (2.0 equiv)
t-BuONO (1.6 equiv)
1,2-dichloroethane, 0 °C, 1 h
82%
Br
Br
Br
Br
Br
MeCN, 60 °C, 1 h
80%
NH2
Br
22
23
NO2
Br
Br
CH2=CHMgBr (3.0 equiv)
TBSOTf (3.0 equiv)
21
NaH (4.0 equiv)
-40 °C
32%
Br
N
Et3N (2.0 equiv)
H
Br
Br
25
THF, 0 °C
78%
24
Scheme 5. Synthesis of 5,6,7-tribromoindole via Bartoli route.

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N. Chandrasoma et al. / Tetrahedron Letters 54 (2013) 913–917
Br
Br
OsO4 (0.1 equiv)
NaIO4 (15 equiv)
20
NMO (5.0 equiv)
THF/H2O (1.5:1), rt
75%
THF/H2O (3.3:1), rt
99%
OHC
+
N
N
TBS
33
TBS
HO
Br
34
CHO
OH
Br
H
EtSH
Ni (R)
BF3•OEt2
-78 °C to rt
74%
acetone
(EtS)2HC
N
N
H
N
H
rt
H
35
CH(SEt)2
19, 16-31%
36, 30-36%
Scheme 8. Raney nickel reduction of 35.
Br
Br
NaBH4 (10 equiv)
MsCl (2.2 equiv)
34
Et3N (4.0 equiv)
CH2Cl2, 0 °C to rt
THF, 0 °C, 15 min
86%
MsOH2C
Br
HOH2C
N
N
TBS
TBS
82%
CH2OMs
CH2OH
37
Br
38
NaI (15 equiv)
TBAF (2.0 equiv)
powdered Zn (60 equiv)
glyme, 90 °C (sealed tube), 8 h
58%
THF, rt, 2 h
82%
N
N
H
TBS
19
39
Scheme 9. Fujimoto reduction of 34.
Acknowledgments
Br
SnBu3
40
Pd2(dba)3 (2.5 mol%)
AsPh3 (10 mol%)
THF
MW, 150 °C, 23 min
73%
We acknowledge support of this work by the National Institutes
of Health, Grant R01 GM069711 (K.R.B.). We also acknowledge
additional support of this work by the National Institutes of Health,
The University of Kansas Chemical Methodologies and Library
Development Center of Excellence (KU-CMLD), NIGMS, Grant P50
GM069663. We further acknowledge ACS Project SEED for a sum-
mer research internship for Ms. Susana Suarez. We thank Dr. Chris
Sakai for technical assistance with this project.
N
N
H
H
19
( )-cis-Trikentrin B
Scheme 10. Final step: Stille cross-coupling.
our work (Scheme 9). The dialdehyde 34 was reduced with sodium
borohydride, the resulting diol 37 mesylated, and then reduced un-
der the Fujimoto protocol (NaI, 15 equiv; powdered Zn (60 equiv);
glyme, 90 °C, sealed tube, 8 h) to afford the intermediate 39 (TBS
protected 19) in an improved and reliable 58% yield. Desilylation
was accomplished with TBAF (2.0 equiv; THF, rt, 2 h) to give the
5-bromoindole 19 in 82% yield.
The last step to complete the synthesis initially involved a plan
to generate the Grignard reagent from 39, followed by reaction
with butyraldehyde and then acid-catalyzed elimination. Surpris-
ingly, all attempts with the Grignard reaction or the alternative
metal–halogen exchange at this position were unsuccessful. Final-
ly, we turned to the Stille cross-coupling for introducing the bute-
nyl side chain (Scheme 10).
Supplementary data
Supplementary data (1H and 13C NMR data for all new com-
pounds reported and experimental details for their preparation
can be found under supplementary material as a PDF document)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.11.125.
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