Total synthesis of (+)-trans-trikentrin A

Article abstract of DOI:10.1002/chem.201202413

Several syntheses have already been reported for cis-trikentrins and herbindoles, which are indole alkaloids unsubstituted at the C2 and C3 positions that bear a trans-1,3-dimethylcyclopentyl unit. Herein, we describe the first asymmetric and stereoselective synthesis of the more challenging trans-trikentrin A as its naturally occurring isomer. Different approaches were investigated and the strategy of choice was a combination of an enzymatic kinetic resolution and a thallium(III)-mediated ring contraction. The antiproliferative activities of the natural product and related intermediates have been tested against human tumor cell lines, leading to the discovery of new compounds with potent antitumor activity. Simple target? Take a look again! The first stereoselective synthesis of a trans-trikentrin is described (see scheme). In contrast, all cis-related natural products have already been synthesized. An enzymatic kinetic resolution and a ring contraction are the key steps. Potent antitumor compounds have been discovered during this study. Copyright

Full text of DOI:10.1002/chem.201202413

DOI: 10.1002/chem.201202413
Total Synthesis of (+)-trans-Trikentrin A
Iris R. M. Tꢀbꢀka,[a] Giovanna B. Longato,[b] Marcus V. Craveiro,[a, c]
Jo¼o E. de Carvalho,[b] Ana L. T. G. Ruiz,[b] and Luiz F. Silva, Jr.*[a]
Abstract: Several syntheses have al-
ready been reported for cis-trikentrins
and herbindoles, which are indole alka-
loids unsubstituted at the C2 and C3
positions that bear a trans-1,3-dime-
thylcyclopentyl unit. Herein, we de-
scribe the first asymmetric and stereo-
selective synthesis of the more chal-
lenging trans-trikentrin A as its natural-
ly occurring isomer. Different ap-
proaches were investigated and the
strategy of choice was a combination of
an enzymatic kinetic resolution and a
thalliumACTHNUGTERNNU(G III)-mediated ring contrac-
tion. The antiproliferative activities of
the natural product and related inter-
mediates have been tested against
human tumor cell lines, leading to the
discovery of new compounds with
potent antitumor activity.
Keywords: antitumor activity · ki-
netic resolution · ring contraction ·
total synthesis · trikentrin
Introduction
Natural products possess a unique ability to act as bioactive
agents against a variety of targets due to their potentially
relevant, biosynthetically molded structures.[1] Among them,
marine natural products display versatile structural features
that are seldom encountered in compounds from terrestrial
sources.[2] Accordingly, the success rate of clinically useful
discovered drugs among tested marine natural products
(1 drug per 3140 tested compounds) is higher than the in-
dustry average (1 in 5000–10000).[3] Natural products incor-
porating indole rings, which are often found in compounds
from the marine environment, have inspired the develop-
ment of several important synthetic methods and useful
drugs.[4] Usually, indoles are substituted at their very reac-
tive 2- and 3-positions.[4a] However, a few alkaloids lack sub-
stituents at these positions. The most important ones are
probably trikentrins and herbindoles,[5] which have been iso-
lated from sponges.[6] In addition, a substituted five-mem-
bered ring incorporating two stereocenters is fused to the
indole moiety (Figure 1). These cyclopenta[g]indoles show
Figure 1. Structures of trikentrins and herbindoles.
antimicrobial activity,[6a] cytotoxicity against KB cells,[6b] and
are fish antifeedants.[6b] Related compounds can inhibit the
human nonpancreatic secretory phospholipase A2.[7]
Due to their challenging structural features and promising
biological activities, an increasing interest in the chemical
synthesis of trikentrins and herbindoles has been apparent
in recent years.[5,8,9] There have been several total syntheses
of the alkaloids containing a cis-1,3-dimethylcyclopentyl
unit.[5] Asymmetric syntheses of all cis-trikentrins and her-
bindoles have recently been accomplished.[8a,b] However, to
the best of our knowledge, there is as yet no stereoselective
synthesis for the more challenging trans-trikentrins.[9] The
reported synthesis of (ꢀ)-trans-trikentrin A is stereorandom
because the target molecule was obtained together with
(ꢀ)-cis-trikentrin A.[8m] The previous racemic syntheses of
trans-trikentrin A also have serious problems associated
with the formation of the trans-1,3-dimethylcyclopentyl unit,
[a] I. R. M. Tꢀbꢀka, Dr. M. V. Craveiro, Prof. L. F. Silva, Jr.
Instituto de Quꢁmica, Universidade de S¼o Paulo
CP 26077 CEP 05513-970 S¼o Paulo-SP (Brazil)
Fax : (+55 11) 3815-5579
E-mail: luizfsjr@iq.usp.br
[b] G. B. Longato, Prof. J. E. de Carvalho, Dr. A. L. T. G. Ruiz
Centro Pluridisciplinar de Pesquisas Quꢁmicas
Biolꢂgicas e Agrꢁcolas, Universidade Estadual de Campinas
Campinas-SP (Brazil)
[c] Dr. M. V. Craveiro
Present address: Universidade Federal de S¼o Paulo
R. Prof. Artur Riedel
275 CEP 09972-270 Diadema-SP (Brazil)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202413.
16890
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Chem. Eur. J. 2012, 18, 16890 – 16901

FULL PAPER
and the best ratio was cis/trans=1:1.[8l] In other syntheses,
the trans isomer was the minor component (4:3[8m] and
55:40[8k]). We developed a protocol for the synthesis of
This strategy was based on our racemic synthesis of trans-tri-
kentrin A.
Our first target was the preparation of 2, which was ob-
tained in four steps from 5, by using the Bartoli reaction to
construct the indole ring (Scheme 3).[14] The preparation of
trans-1,3-disubstituted indanes through thallium
(III)[10a,e]- or
ACHTUNGTRENNUNG
iodine
ACHTUNGTRENNUNG
dronaphthalenes. This reaction was applied in the synthesis
of (ꢁ)-trans-trikentrin A[9a] and of other small mole-
cules.[10c,d,h] In this context, we describe herein the first asym-
metric synthesis of (+)-trans-trikentrin A, using an enzymat-
ic resolution and a ring-contraction reaction as key steps.
The chemical synthesis of small-molecule natural products
has an important role in the discovery of new anticancer
candidates.[11] Considering the potential biological activity of
indole compounds,[12] the antiproliferative activities of the
target molecule and analogues have been investigated, lead-
ing to the discovery of some potent antitumor compounds.
Scheme 3. Preparation of bromoindole 2. a) NaBH4, MeOH; b) Ph3P, I2,
imidazole, CH2Cl2; c) NaBH4, DMSO; d) CH2=CHMgBr, THF.
6 was described in one step from 1-bromo-4-ethylbenzene
by nitration, which gave a mixture of two products from
which 6 could be obtained in 35% yield after separation of
the isomers.[8a] Nevertheless, in three steps and within a few
hours, compound 6 was obtained in 88% overall yield on a
10 g scale.
The asymmetric reduction of a,b-unsaturated esters can
be performed by using cobalt semicorrins as catalysts and
NaBH4 as the reducing agent.[15a,b] Pfaltz and co-workers
have also developed various iridium catalysts to perform the
asymmetric hydrogenation of nonfunctionalized alke-
nes.[15c–e] Several iridium catalysts[15f–j] and a cobalt-com-
plexed semicorrin were tested under different conditions for
the asymmetric reduction of 12 (Figure 2 and Table 1),
Results and Discussion
Our retrosynthesis of (+)-trans-trikentrin A was centered on
the use of a ring contraction of the cyclohexene derivative 1
(Scheme 1). This transformation is probably the most effi-
Scheme 1. Ring-contraction approach for (+)-trans-trikentrin A.
PG=protecting group.
cient method for constructing the required trans-1,3-disubsti-
tuted indane ring.[10,13] From the outset, we envisaged that
the tricyclic intermediate 1 could be prepared in an optically
active fashion from bromoindole 2 by several routes. In
practice, we had to struggle through different alternatives to
finally achieve this goal.
The first approach toward the synthesis of 1 was through
an asymmetric hydrogenation of 4 that would lead to alkene
1 after homologation, intramolecular acylation, and the in-
terconversion of functional groups. Alkene 4 would be ob-
tained from bromoindole 2 by a Heck coupling (Scheme 2).
Figure 2. Catalysts for asymmetric hydrogenation. COD=1,5-cycloocta-
diene.
which was obtained from indole
2 by protection with benzyl bro-
mide followed by a Heck reac-
tion (Scheme 4). However, low
conversions and ee values were
usually observed. The best
result was obtained by using
the catalyst 9, which gave the
Scheme 2. First retrosynthetic approach to access cyclic alkene 1. FGI=functional group interconversion.
desired product 13 with 57% ee
Chem. Eur. J. 2012, 18, 16890 – 16901
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16891

L. F. Silva, Jr. et al.
Table 1. Conditions for asymmetric reduction of 12.
ate olefin would form 15
(Scheme 5).
Entry
Cat.
[mol%]
P
T
t
Solvent
Product (Conversion [%]; ee [%])[a]
A
E
[8C]
[h]
Among the available meth-
ods for this transformation, the
most suitable to obtain 19 ap-
peared to be that described by
Dambacher et al.[16] The re-
quired intermediate 18 was pre-
pared by a convergent strategy
that involved Heck coupling of
2 and the chiral olefin 17[17] fol-
lowed by protection. Alkene 17
was obtained from commercial-
ly available pyrrolidinone 16
and freshly prepared acryloyl
chloride.[18] Unfortunately, the
desired product 19 was not de-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Pd/C (10)
Pd(OH)2/C (10)
7 (1)
7 (1)
7 (5)
7 (1)
8 (1)
8 (1)
8 (5)
8 (1)
9 (1)
9 (1)
9 (5)
100
30
50
50
50
70
50
50
50
70
50
50
50
70
50
50
70
RT
RT
RT
40
40
55
RT
40
40
55
RT
40
40
55
RT
40
55
2
14
2
16
14
62
2
16
14
62
2
16
14
62
2
THF
THF
Recovered s.m.
Recovered s.m./13 (2:1; ꢀ)
Recovered s.m.
(S)-13 (10; n.d.)
(S)-13 (10; 36)
(S)-13 (10; 24)
Recovered s.m.
(S)-13 (9; n.d.)
(S)-13 (15; 6)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH/DMF
(S)-13 (10; 24)
Recovered s.m.
(S)-13 (16; n.d.)
(S)-13 (23; 57)
(S)-13 (15; 30)
Recovered s.m.
(S)-13 (9; ꢀ)
9 (1)
10 (1)
10 (2)
10 (2)
11 (10)[b]
16
62
48
13 (9; ꢀ)
atmospheric
RT
Recovered s.m.
tected
in
any
reaction
[a] Suggested absolute configuration based on the literature.[15] [b] Complexed with CoCl2. NaBH4 (2 equiv)
was used as reducing agent.
(Scheme 6).
Our third approach involved
an aryl coupling to an iron com-
plex.[19a] Intermediate 1 would
be accessed after functional group interconversion and intra-
molecular acylation of 20. An aryl coupling of indoline 21
with an iron complex[20] obtained from a lactic acid deriva-
tive would form ester 20 in
a convergent manner
(Scheme 7).
Indoline 27 was prepared from 2 in three nonoptimized
steps. Treatment of 27 with sBuLi led to metallation of the
indole, as confirmed by interception with DMF (see the
Supporting Information for details). Complex 26 was ob-
tained from the lactic acid derivative 22 by an adapted
route.[19b] Oxidation of alcohol 23 to aldehyde 24 could also
be achieved with SIBX (stabilized 2-iodoxybenzoic acid),[21]
but in lower yield (57%) and after a delicate purification.
The coupling of cuprate 29 and the iron complex 26 did not
take place under any of the investigated conditions (Sche-
me 8).[19c] These three approaches taught us that powerful
reactions for benzenic systems became inefficient for the
corresponding substrates with indole-type rings.
Scheme 4. First approach: asymmetric hydrogenation . a) KOH, BnBr,
DMSO; b) ethyl crotonate, PdCl2, P(o-tol)3, Et3N, MeCN; c) asymmetric
hydrogenation; d) DIBAL, toluene; e) catalyst 7, 8, 9, or 10, H2 (50 bar).
Bn=benzyl; s.m.=starting material; o-tol=ortho-tolyl; DIBAL=diiso-
butylaluminum hydride.
AHCTUNGTRENNUNG
Biocatalysis has recently been used in various total syn-
theses of natural products.[22a,b] The mild conditions usually
required for enzymatic resolution, coupled with the high se-
lectivity and substrate specificity of enzymes,[22b,c] make it a
powerful tool in organic synthesis[22b] and in industry.[22d]
at 23% conversion (Table 1, entry 13). We also attempted
without success the hydrogenation of compounds related to
12, such as the alcohol 14. Steric hindrance due to the
benzyl group may have prevented the catalyst–H2 complex
from reaching the double bond
of the substrate. Additionally,
the low reactivities of 12 and 14
may have been due to catalyst
poisoning by the indole moiety.
Our second approach was re-
lated to an asymmetric conju-
gate addition to obtain 3 from
15. A chiral auxiliary would be
used in the conjugate addition,
and a Heck coupling between
bromoindole 2 and an appropri- Scheme 5. Second retrosynthetic approach toward cyclic alkene 1.
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Chem. Eur. J. 2012, 18, 16890 – 16901

Trikentrin Synthesis
FULL PAPER
Our fourth and successful approach toward the synthesis of
(+)-trans-trikentrin A was based on lipase-mediated kinetic
resolution of ester 32, obtained from 2 (Scheme 9).
The stereocenter of ester 34 is not on the a-, but on the b
carbon atom, that is, more distant from the reactive center
(Scheme 10). This not only makes the kinetic resolution
more challenging, but also reduces the chances of finding
suitable methods to racemize the nonreactive enantiomer.
We performed an enzyme screening to find the optimal con-
ditions, and ester 34 was the substrate of choice as its syn-
thesis has been reported previously,[9a] thus avoiding the
need for optimization. The (S)-selective lipase-mediated hy-
drolysis of related substrates has been reported to proceed
with high ee by using Pseudomonas cepacia lipase (PCL).[23]
Such (S)-selectivity of PCL has also been reported for the
hydrolysis of b-amino esters.[24] We assumed at this point
that the acid obtained from the kinetic resolution by the
screened lipases would be the (S)-enantiomer. The (S)-enan-
tioselectivity would only be confirmed at the end of the syn-
thesis, by comparing the optical rotation of the target mole-
cule with that of the natural
Scheme 6. Second approach: asymmetric conjugate addition. a) 1) nBuLi,
2) acryloyl chloride; b) 17, PdACTHUNGTRENNG(U OAc)2, PACHTUNGTNERN(UNG o-tol)3, Et3N, DMF; c) Boc2O,
DMAP, CH2Cl2; d) CuI, MeLi. Boc=tert-butoxycarbonyl; DMAP=4-di-
methylaminopyridine.
product. After much experi-
mentation (Table 2), we found
that (S)-35 could be obtained
with 99% ee in 38% yield by
using the enzyme Amano PS-
CII (Table 2, entry 6), which is
a formulation of PCL immobi-
lized on a ceramic substrate.
Scheme 7. Third retrosynthetic approach to obtain alkene 1.
Shorter (Table 2, entry 5) or
longer (Table 2, entry 7) reaction times were found to de-
crease the yield, and decomposition products were formed
after a 109 h cycle. However, when scaling up we found that
the production of this enzyme has been discontinued. In a
second screening, PS-IM (PCL immobilized on diatoma-
ceous earth) gave (S)-35 with 99% ee in 32% isolated yield
(Table 2, entry 10). It is known that the amount of water in
the reaction mixture determines the direction of lipase-cata-
lyzed reactions.[25a] As hydrolysis is favored over transesteri-
fication in the presence of water, the water content in the
reaction mixture was increased (Table 2, entries 11–13).
However, even after longer reaction times (Table 2,
entry 12), lower yields were obtained. Compound (S)-35 has
the potential to be used in the total synthesis of (+)-cis-tri-
kentrin A.[8a]
Considering that a Boc group would be better than Bn in
the ring contraction,[26] we investigated the preparation of
(S)-39. Unfortunately, neither the reduction of 36 nor the
resolution of 38 gave the desired product in a practicable
manner (Scheme 11). It is known that, as is the case for the
majority of enzymes, the enantioselectivity of PCL is highly
substrate-dependent, and small structural modifications can
significantly alter the ee.[25] Substrate recognition is driven
by diastereoselective nonbonding interactions formed by the
substrate at the active site of the enzyme, where aromatic
rings are optimally accommodated. Also, hydrolysis can be
prevented by steric hindrance in the vicinity of the active
Scheme 8. Third approach: aryl coupling. a) TIPSCl, imidazole, DMF;
b) LiBH4, MeOH, Et2O; c) IBX, EtOAc; d) ethyl phosphonoacetate,
NaH, THF; e) [Fe2(CO)9], Et2O; f) NaCNBH4, AcOH; g) Boc2O,
DMAP, CH2Cl2; h) 1) nBuLi, THF, 2) H3O+; i) sBuLi, TMEDA, Et2O;
j) CuBr·SMe2; k) 26; l) CAN. TIPS=triisopropylsilyl; IBX=2-iodoxy-
benzoic acid; TMEDA=N,N,N’,N’-tetramethylethylenediamine; CAN=
ceric ammonium nitrate.
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16893

L. F. Silva, Jr. et al.
Having established a reliable
procedure to obtain (S)-35, we
worked toward its homologa-
tion. After achieving good re-
sults with a model substrate by
using the Kowalski homologa-
tion,[28] the relevant conditions
were applied to (ꢁ)-34. The re-
Scheme 9. Fourth and successful retrosynthetic approach to access alkene 1.
Table 2. Enzyme screening for kinetic resolution[a] of ester 34.
quired dibromoketone 40 was
prepared in good yield. Howev-
er, the next step did not pro-
ceed under any of the conditions tested
(Scheme 12). As an excess of nBuLi was needed,
reactive positions C2 and C3 may have been metal-
lated, leading to several unidentified products.
The desired homologated acid (S)-42 was ob-
tained in 73% overall yield by a robust four-step
sequence from (S)-35. Acid (S)-42 was cyclized to
yield (S)-43 and the protecting group was changed
to the electron-withdrawing Boc[29] to afford (S)-45,
which was reduced and dehydrated to yield (S)-46
(Scheme 13).
The cyclic alkene (S)-46 was treated with thalli-
um trinitrate trihydrate (TTN) and NaBH4 to pro-
mote the ring contraction. The aldehyde formed in
situ was reduced to alcohol 47 to avoid any epimeri-
zation. Remarkably, electrophilic TlIII was found to
react with the alkene without disturbing the highly
reactive indole ring.[26] Additionally, only the trans
diastereomer was formed during this rearrange-
ment. The alcohol moiety of 47 was then reduced
to the corresponding alkane, delivering (+)-trans-
trikentrin A ([a]D25 = +248, c=0.00125 in CHCl3;
Scheme 14). The optical rotation of the target mole-
cule was equivalent to the reported value for the
natural product,[6a] thus confirming the (S)-selectivi-
ty of PCL towards ester 34 during the kinetic reso-
lution and indicating that there was no epimeriza-
tion in any reaction after the resolution.
The tosylate reduction and Boc deprotection of
48 were not expected to be accomplished in a single
step, because Boc groups are usually stable in the
presence of NaBH4.[30] N-Boc-amines have also
been reported to be deprotected in the presence of
water at 1008C, acting as an acid–base catalyst.[31]
Moreover, the neat thermolysis of Boc groups has
been reported, with the temperature varying ac-
cording to the substrate structure.[8b,32] We believe
that when heating 48, the water present in DMSO
might have favored the deprotection. The presence
of NaBH4 coupled with a long heating time may
also have played a role in producing the observed
Entry
Enzyme
Solvent
Yield of (S)-35
[%]
19[b]
8[b]
26
ee
[%]
1
2
3
4
5
6
7
8
9
PS-D
PS-D
PS-CII
PS-CII
PS-CII
PS-CII
PS-CII
PS-IM
PS-IM
PS-IM
PS-IM
PS-IM
PS-IM
PS-IM
CALB
CALB
Et2O
DIPE
Et2O
97
99
95
99
99
99
99
99
99
99
99
99
99
99
–
0
–
0
0
–
–
0
0
–
0
27
3
–
0
4
0
91
0
97
3
–
0
6
DIPE
DIPE
DIPE
DIPE
Et2O
DIPE
DIPE
DIPE
DIPE
DIPE
DIPE
Et2O
DIPE
phosphate buffer[i]
Et2O
DIPE
phosphate buffer[i]
DIPE
Et2O
DIPE
Et2O
DIPE
Et2O
DIPE
Et2O
DIPE
Et2O
34
27[c,d]
38[c]
12[c,e]
4[b]
21[b]
32[c]
15[f]
23[c,f]
7[g]
21[h]
n.d.
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
CALB
PPL
PPL
PPL
n.d.
1
1
n.d.
n.d.
1
1
n.d.
1
1
1
n.d.
1
1
1
21
1
2
1
n.d.
1
Novozym 435
Pseudomonas cepacia (free)
Pseudomonas cepacia (free)
Pseudomonas sp. in cellulose
Pseudomonas sp. in cellulose
Penicillium camembertii
Penicillium camembertii
Mucor meihei
Mucor meihei
Aspergillus niger
Aspergillus niger
Pseudomonas fluorescens
Pseudomonas fluorescens
Mucor javanicus
Mucor javanicus
Candida cylindracea
Candida cylindracea
Candida rugosa
Candida rugosa
DIPE
Et2O
DIPE
Et2O
DIPE
Et2O
DIPE
Et2O
1
1
DIPE
0
[a] 1 mg enzyme per 1 mg substrate, 0.5 molLꢀ1, H2O (4 equiv), 65 h. [b] Isolated
yields. Other yields were calculated by HPLC. [c] After 2 cycles on a 0.3 mmol scale.
[d] 43 h cycle. [e] 109 h cycle, decomposition products observed. [f] 10 equivalents of
H2O were used. [g] 20 equivalents of H2O were used. [h] 95 h cycle. [i] 1 mg enzyme
per 1 mg of substrate, 1 molLꢀ1 phosphate buffer, pH 7, MeOH, 408C, 65 h.
site.[27] The reason why the kinetic resolution of ester 38 was
not observed to any extent may be the replacement of the
benzyl group by Boc, as one less aromatic ring was available
to facilitate the substrate accommodation inside the active
site of the enzyme.
results. A qualitative experiment was set up to identify the
determining factor in the Boc deprotection of 48. N-Boc
indole 49 was heated in parallel reactions that were followed
by TLC (Scheme 15). Reactions a) and c) led exclusively to
the deprotected indole 50, but heating 49 in anhydrous
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Chem. Eur. J. 2012, 18, 16890 – 16901

Trikentrin Synthesis
FULL PAPER
Scheme 10. Fourth and successful approach: kinetic resolution of 34 by
lipase. a) KOH, BnBr, DMSO; b) methyl crotonate, PdCl2, P
Et3N, MeCN; c) Mg, MeOH; d) kinetic resolution.
ACHTUNGTNER(NUNG o-tol)3,
Scheme 13. Preparation of tricyclic indole (S)-46. a) BH3·SMe2, MeOH,
Et2O; b) MsCl, DMAP, pyridine, CH2Cl2; c) KCN, DMSO; d) KOH, eth-
ylene glycol, H2O; e) TFA, TFAA; f) AlCl3, anisole; g) Boc2O, DMAP,
CH2Cl2; h) NaBH4, MeOH; i) H3PO4, DMF. Ms=mesyl; TFA=trifluoro-
acetic acid; TFAA=trifluoroacetic anhydride.
Scheme 11. Tentative preparation of (S)-39. a) Ethyl crotonate, PdCl2, P-
(o-tol)3, Et3N, MeCN; b) Mg, MeOH; c) Boc2O, DMAP, CH2Cl2; d) PS-
ACHTUNGTRENNUNG
CII, DIPE, H2O. DIPE=diisopropyl ether.
Scheme 14. Final steps toward (+)-trans-trikentrin A. a) 1) TTN, MeCN,
2) NaBH4; b) TsCl, Et3N, pyridine, CH2Cl2; c) NaBH4, DMSO. TTN=
thalliumACTHUNRTGNEUNG(III) nitrate trihydrate; Ts=tosyl; b.r.s.m.=based on recovered
starting material.
Scheme 12. Kowalski homologation of a model compound and tentative
preparation of 41. a) TMP, nBuLi, CH2Br2, THF; b) 1) HMDS, nBuLi,
2) nBuLi, 3) MeOH/HCl. TMP=2,2,6,6-tetramethylpiperidine; HMDS=
hexamethyldisilazane.
Scheme 15. Tested conditions for the deprotection of 49.
DMSO without NaBH4 did not form 50 and a decomposi-
tion product was observed. Thus, either water or NaBH4 is
capable of deprotecting indole substrates upon heating in
DMSO.
values,[33] the tested compounds showed moderate cytostatic
effects, except for 52, which showed only weak activity, and
55, which appeared to be inactive. The moderately active
compounds displayed different selectivity profiles. The ex-
tended conjugation present in 55 would seem to dramatical-
ly impair its activity, as the structurally related compound 37
showed moderate activity. Compounds (S)-43 and (S)-44,
which differ only in the protecting group, showed moderate
The indole 54 was synthesized from alkene 51[26] to broad-
en the variety of analogues to be tested against human
tumor cell lines (Scheme 16).
The in vitro antiproliferative activities of the target mole-
cule and related compounds were evaluated toward human
tumor cell lines (Table 3). According to the mean logGI50
Chem. Eur. J. 2012, 18, 16890 – 16901
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16895

L. F. Silva, Jr. et al.
Table 3. Antiproliferative activities (GI50, mgmLꢀ1) of (+)-trans-trikentrin A and its analogues.[a]
Doxo-ru-
Entry
bicin
37
3.1
4.3
5.6
55
(S)-43
(S)-44
52[b]
54
(+)-trans-tri-
kentrin A
(ꢁ)-trans-tri-
kentrin A
U251
MCF-7
NCI-
0.106
0.062
3.842
>250
>250
>250
3.0
6.9
2.6
18.9
21.4
0.42
25.6
26.3
31.5
4.4
18.1
0.36
19.7
2.8
2.5
N.T.
29.0
9.2
ADR/RES
OVCAR-3
786-0
NCI-H460
PC-3
UACC-62
HT-29
HaCat
0.336
0.139
0.080
0.146
N.T.
7.4
4.0
7.4
10.2
N.T.
N.T.
5.3
>250
>250
>250
>250
N.T.
N.T.
>250
>2.40
3.1
10.6
8.1
17.2
20.8
10.5
7.6
N.T.
N.T.
8.1
25.5
28.5
41.4
40.4
N.T.
N.T.
22.1
1.47
17.4
19.0
18.2
9.8
N.T.
8.9
3.1
12.2
21.7
6.6
N.T.
N.T.
4.5
2.8
22.1
2.8
22.6
3.7
9.6
N.T.
1.07
6.1
N.T.
N.T.
4.7
N.T.
0.115
ꢀ0.350
4.2
0.86
Mean
LogGI50
0.74
0.70
0.95
0.82
[a] U251: glioma; MCF-7: breast; NCI-ADR/RES: ovarian resistant to multiple drugs; OVCAR-3: ovarian; 786-0: kidney; NCI-H460: lung, nonsmall
cells; PC-3: prostate; UACC-62: melanoma; HT-29: colon; VERO: green monkey epithelial kidney cell; HaCat: human keratinocyte, immortalized
normal cell; N.T.: not tested.
Experimental Section
7-Bromo-4-ethyl-1H-indole (2):
A
Schlenk flask was loaded with
6
(480 mg, 2.11 mmol) under N2 atmos-
phere, anhydrous THF (50 mL) was
added, and the solution was cooled to
Scheme 16. Concomitant reduction and deprotection toward 54. a) 1) TTN, MeCN, 2) NaBH4; b) TsCl, Et3N,
CH2Cl2; c) NaBH4, DMSO.
ꢀ458C. A 1 molLꢀ1 solution of vinyl-
magnesium bromide in THF (7.40 mL,
7.40 mmol, 3.5 equiv) was added drop-
wise. After 45 min under stirring, a sa-
activity. However, (S)-44 inhibited the growth of adryamy-
cin-resistant ovarian tumor cells (NCI-ADR/RES) more po-
tently (GI50 =0.42 mgmLꢀ1) than that of other cell lines
(GI50 from 7.6 to 21.4 mgmLꢀ1). A similar profile was ob-
served for indole 54 (GI50 =0.36 mgmLꢀ1 for NCI-ADR/
RES; other cell lines: GI50 from 4.2 to 19.0 mgmLꢀ1). It is
important to note that compound 54 can be prepared in
only seven steps from 1-tetralone. (+)-trans-Trikentin A
proved to be slightly more active (mean logGI50 =0.82) than
(ꢁ)-trans-trikentin A (mean logGI50 =1.07).
turated aqueous solution of NH4Cl was slowly added and the mixture
was allowed to warm to RT. The aqueous phase was extracted with Et2O
and the organic layer was washed with a saturated aqueous solution of
NH4Cl and with brine and dried over anhydrous MgSO4. The solvent was
evaporated under vacuum and the remaining crude material was purified
by flash chromatography (hexanes/EtOAc, 10:1!9:1) to afford 2[9a]
(300 mg, 1.34 mmol, 63%) as a brown oil.
1-Bromo-4-ethyl-2-nitrobenzene (6): NaBH4 (2.355 g, 61.97 mmol,
1.5 equiv) was slowly added to a stirred solution of the starting acetophe-
none 5 (10.080 g, 41.31 mmol) in MeOH (80 mL) at 08C, and the mixture
was allowed to warm to RT. After stirring for 30 min, H2O was added
and the aqueous layer was extracted with EtOAc. The organic phase was
washed with brine and dried over anhydrous MgSO4. The solvent was
evaporated under vacuum and the remaining crude alcohol was dissolved
in CH2Cl2 (200 mL). Ph3P (16.235 g, 61.97 mmol, 1.5 equiv) and imidazole
(4.214 g, 61.97 mmol, 1.5 equiv) were then added and the mixture was
cooled to 08C. Molecular iodine (15.740 g, 61.97 mmol, 1.5 equiv) was
added, the cold bath was removed, and after stirring for 3 h, H2O was
added and the mixture was extracted with CH2Cl2. The organic layer was
washed with brine and dried over anhydrous MgSO4. The solvent was
evaporated under reduced pressure and the crude product was kept
under high vacuum for 1.5 h. The product was then dissolved in DMSO
(150 mL) and the solution was cooled to 08C. Sodium borohydride
(3.140 g, 82.62 mmol, 2 equiv) was slowly added, the reaction mixture
was allowed to warm to RT and stirred for 30 min, and then cooled to
08C once more. H2O was added and the aqueous phase was extracted
with EtOAc. The organic phase was washed with brine, dried over anhy-
drous MgSO4, and the solvent was evaporated under reduced pressure to
Conclusion
The first total synthesis of (+)-trans-trikentrin A has been
achieved by using a kinetic resolution performed by a lipase
and a thalliumACHTUNGTRENNUNG(III)-mediated ring contraction as key steps.
The antiproliferative activities of several molecules have
been tested, and the results pointed to (S)-44 and 54 as
promising lead compounds against drug-resistant ovarian
cell lines. The synthesis of (+)-cis-trikentrin A can be envis-
aged from (S)-acid 35. A short synthesis of this natural
product and the cytotoxic activities of related intermediates
are under evaluation.
16896
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16890 – 16901

Trikentrin Synthesis
FULL PAPER
afford the crude product as a yellow solid. This product was dissolved in
the minimum volume of CH2Cl2 and then a mixture of hexane/Et2O (1:1;
100 mL) was added. After gentle shaking, Ph3PO started to precipitate.
The mixture was then filtered through a silica pad with Et2O, and the
pad was washed with Et2O until no more product was eluted, as moni-
tored by TLC. This procedure removed most of the Ph3PO formed as a
byproduct. The eluent was collected and concentrated under reduced
pressure, and the crude product was purified by column chromatography
(hexanes/EtOAc, 9:1) to afford compound 6[9a] (8.393 g, 36.49 mmol,
88% over three steps) as a yellow oil.
an N2-filled Schlenk flask and anhydrous THF (0.2 mL) was added. The
solution was cooled to ꢀ788C and a 2.03 molLꢀ1 solution of nBuLi in
hexanes (0.034 mL, 0.070 mmol, 1.2 equiv) was added dropwise. After
stirring for 2 h, the mixture was allowed to warm to RT. Saturated aque-
ous NH4Cl solution was then added dropwise and the resulting mixture
was extracted with Et2O. The organic phase was washed with brine and
dried over anhydrous MgSO4. The solvent was evaporated under reduced
pressure and the remaining crude product was purified by flash chroma-
tography (hexanes/EtOAc, 10:1!9:1) to afford 27 (13 mg, 0.053 mmol,
91%) as a light-yellow oil that solidified upon standing. M.p. 39–428C;
1H NMR (300 MHz, CDCl3): d=7.69 (m, 1H), 7.12 (t, J=7.8 Hz, 1H),
6.79 (d, J=7.5 Hz, 1H), 3.98 (t, J=8.7 Hz, 2H), 3.02 (t, J=8.7 Hz, 2H),
2.55 (q, J=7.7 Hz, 2H), 1.56 (s, 9H), 1.20 ppm (t, J=7.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=152.5, 142.9, 140.0, 127.5, 124.6, 121.3,
117.2, 112.1, 82.4, 47.4, 28.3 (3C), 25.7, 13.9 ppm; IR (film): n˜max =3048,
1-Acryloyl-5-trityloxymethylpyrrolidin-2-one (17): An N2-filled Schlenk
flask was loaded with 16 (71 mg, 0.20 mmol) and anhydrous THF (5 mL)
was added. The solution was cooled to ꢀ788C, whereupon a 2 molLꢀ1
solution of nBuLi in hexanes (0.11 mL, 0.22 mmol, 1.1 equiv) was added
dropwise. After stirring for 45 min, acryloyl chloride[18a] (0.02 mL,
0.24 mmol, 1.2 equiv) was added dropwise and the reaction mixture was
stirred for 30 min. Saturated aqueous NH4Cl solution (1 mL) was then
added, the mixture was allowed to slowly warm to RT, and then diluted
with H2O. It was extracted with Et2O, and the organic layer was washed
with brine and dried over anhydrous MgSO4. The solvent was evaporated
under vacuum and the crude product was purified by flash chromatogra-
phy (hexanes/EtOAc, 8:2!7:3) to afford 17 (37 mg, 0.09 mmol, 44%) as
a light-yellow oil that solidified as a white material upon standing. M.p.
133–1358C; [a]2D5 =ꢀ123.28 (c=0.005 gcmꢀ3 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.54 (dd, J=17.1, 10.5 Hz, 1H), 7.37–7.19 (m,
15H), 6.46 (dd, J=17.1, 2.1 Hz, 1H), 5.86 (dd, J=10.5, 2.1 Hz, 1H),
4.56–4.51 (m, 1H), 3.59 (dd, J=9.9, 2.7 Hz, 1H), 3.16 (dd, J=9.9, 2.7 Hz,
1H), 3.05–2.92 (m, 1H), 2.51 (qd, J=9.9, 2.1 Hz, 1H), 2.19–1.96 ppm (m,
2H); 13C NMR (75 MHz, CDCl3): d=176.5, 165.7, 143.6 (3C), 130.6,
129.6, 128.5 (6C), 127.9 (6C), 127.1 (3C), 87.1, 64.0, 56.8, 33.2, 21.2 ppm;
IR (KBr): n˜max =3058, 2930, 1737, 1681, 1231 cmꢀ1; HRMS (ESI): m/z
calcd for [C27H25NO3+Na]+: 434.1732; found: 434.1735.
2968, 2391, 2873, 1703, 1461, 1398 cmꢀ1; LRMS: m/z (%): 247 (3) [M+ ],
C
191 (27), 146 (30), 130 (11), 117 (18), 57 (100), 41 (50); HRMS (ESI): m/
z calcd for [C15H21NO2+H]+: 248.1651; found: 248.1622.
(E)-Methyl 3-(1-benzyl-4-ethyl-1H-indol-7-yl)but-2-enoate (33): The
starting bromoindole 2 (249 mg, 1.111 mmol) was placed in a flask and
DMSO (5 mL) was added. KOH (249 mg, 4.444 mmol, 4 equiv) was
added and the mixture was stirred for 30 min. BnBr (0.16 mL,
1.333 mmol, 1.2 equiv) was added and the resulting mixture was stirred at
RT for 12 h. H2O was used to quench the reaction and then the mixture
was extracted with Et2O. The organic layer was washed with brine and
dried over anhydrous MgSO4. The solvent was evaporated under reduced
pressure, the remaining crude product was redissolved in anhydrous
MeCN (5 mL), and this solution was transferred to a Schlenk flask previ-
ously filled with nitrogen. Methyl crotonate (1.88 mL, 17.776 mmol,
16 equiv), PdCl2 (20 mg, 0.111 mmol, 0.1 equiv),
PACTHUNGTER(NNUG o-tolyl)3 (68 mg,
0.222 mmol, 0.2 equiv), and anhydrous Et3N (5 mL) were then added se-
quentially. The reaction mixture was heated to 1108C and stirred under a
nitrogen atmosphere for 15 h. Brine was then added and the aqueous
layer was extracted with EtOAc. The organic phase was washed with
H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated
under vacuum. The crude product was purified by flash chromatography
(silica gel, 100% hexanes!hexanes/EtOAc, 20:1!10:1!9:1) to afford
33 as a white solid after recrystallization from hexanes containing a drop
of CH2Cl2. M.p. 68–698C; 1H NMR (300 MHz, CDCl3): d=7.23–7.20 (m,
3H), 7.09 (d, J=3.3 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.84–6.80 (m, 3H),
6.65 (d, J=3.3 Hz, 1H), 5.71 (q, J=1.3 Hz, 1H), 5.34 (s, 2H), 3.70 (s,
3H), 2.95 (q, J=7.8 Hz, 2H), 2.28 (d, J=1.3 Hz, 3H), 1.37 ppm (t, J=
7.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=166.8, 156.4, 138.2, 136.5,
131.7, 130.1, 129.4, 128.6 (2C), 127.3, 126.3, 126.3 (2C), 121.8, 119.7,
117.7, 100.6, 52.0, 51.0, 26.0, 21.9, 14.5 ppm; IR (film): n˜max =2966, 1717,
(E)-tert-Butyl 4-ethyl-7-{3-oxo-3-[2-oxo-5-(trityloxymethyl)pyrrolidin-1-
yl]prop-1-enyl}-1H-indole-1-carboxylate (18): A solution of the starting
bromoindole 2 (284 mg, 1.27 mmol) in anhydrous DMF (15 mL) was
added to a Schlenk flask under an N2 atmosphere. The chiral olefin 17
(557 mg, 1.4 mmol, 1.1 equiv),
a
solution of Pd
ACHTUNGRTENUN(NG OAc)2 (28 mg,
0.127 mmol, 0.1 mmol) in DMF (1 mL), a solution of PAHCTUNGRT(EUNNNG o-tolyl)3 (193 mg,
0.64 mmol, 0.5 equiv) in DMF (1 mL), and Et3N (0.66 mL, 5.08 mmol,
4 equiv) were then added sequentially to the stirred solution. The reac-
tion mixture was heated to 1208C and stirred for 10 h. It was then cooled
to RT and diluted with brine (50 mL). The resulting mixture was extract-
ed with EtOAc, and the organic layer was washed with H2O and brine
and dried over anhydrous MgSO4. The solvent was evaporated under re-
duced pressure and the remaining brown oil was used in the next step
without further purification. To this end, it was placed in a Schlenk flask
under N2 atmosphere, anhydrous CH2Cl2 (5 mL) was added, followed by
DMAP (15 mg, 0.127 mmol, 0.1 equiv) and Boc2O (415 mg, 1.91 mmol,
1.5 equiv). After stirring for 1 h, H2O was added and the aqueous layer
was extracted with CH2Cl2. The organic phase was washed with brine
and dried over anhydrous MgSO4. The solvent was evaporated under re-
duced pressure and the crude product was purified by flash chromatogra-
phy (hexanes/EtOAc, 95:5!9:1!8:2!7:3) to afford 18 (631 mg,
0.965 mmol, 76%) as a yellow oil that solidified under vacuum or upon
standing. M.p. 70–728C; [a]2D5 =ꢀ35.88 (c=0.00167 gcmꢀ3 in CHCl3);
1H NMR (300 MHz, CDCl3): d=8.45 (d, J=15.6 Hz, 1H), 7.93 (d, J=
15.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.61 (d, J=3.5 Hz, 1H), 7.40–7.34
(m, 6H), 7.30–7.17 (m, 9H), 6.66 (d, J=3.5 Hz, 1H), 4.65–4.62 (m, 1H),
3.64 (dd, J=9.6, 3.9 Hz, 1H), 3.20 (dd, J=9.6, 2.4 Hz, 1H), 3.07–2.97 (m,
1H), 2.90 (q, J=7.7 Hz, 2H), 2.53 (ddd, J=17.7, 9.6, 1.8 Hz, 1H), 2.19–
1.94 (m, 1H), 1.59 (s, 9H), 1.32 ppm (t, J=7.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=176.5, 166.1, 150.0, 145.6, 143.7 (3C), 139.0, 133.7,
131.1, 128.6 (6C), 128.3, 127.9 (6C), 127.1 (3C), 125.0, 122.2, 121.2, 116.9,
105.5, 87.0, 84.5, 64.3, 56.9, 33.5, 27.9 (3C), 26.0, 21.2, 14.8 ppm; IR
(KBr): n˜max =2971, 1744, 1673, 1609, 1491 cmꢀ1; HRMS (ESI): m/z calcd
for [C42H42N2O5+Na]+: 677.2991; found: 677.2994.
1636, 1200, 1162 cmꢀ1; LRMS: m/z (%): 333 (12) [M+ ], 260 (17), 244 (8),
C
196 (10), 167 (19), 91 (100), 65 (27); HRMS (ESI): m/z calcd for
[C22H23NO2+H]+: 334.1807; found: 334.1820.
Methyl 3-(1-benzyl-4-ethyl-1H-indol-7-yl)butanoate (34): Anhydrous
MeOH (7.5 mL) and Mg0 (180 mg, 7.54 mmol, 10 equiv) were added to a
flask containing the ester 33 (251 mg, 0.754 mmol). The mixture was
slowly heated and after heating at reflux for 13 h it had undergone a
color change from light translucent yellow to milky white. After cooling
to RT, 10% HCl solution was added until gas evolution stopped. The
aqueous layer was extracted with EtOAc and the organic layer was
washed with a saturated solution of NaHCO3 and with brine, dried over
anhydrous MgSO4, and concentrated under vacuum. The crude product
was purified by flash chromatography (hexanes/EtOAc, 10:1!9:1) to fur-
nish 34 (243 mg, 0.725 mmol, 96%) as
a
light-yellow oil. 1H NMR
(300 MHz, CDCl3): d=7.28–7.17 (m, 3H), 7.09 (d, J=7.2 Hz, 1H), 6.96–
6.92 (m, 4H), 6.61 (d, J=3.2 Hz, 1H), 5.76 (d, J=17.4 Hz, 1H), 5.51 (d,
J=17.4 Hz, 1H), 3.88–3.76 (m, 1H), 3.57 (s, 3H), 2.95 (q, J=7.5 Hz,
2H), 2.60 (dd, J=15.3, 5.4 Hz, 1H), 2.45 (dd, J=15.3, 9.2 Hz, 1H), 1.36
(t, J=7.5 Hz, 3H), 1.04 ppm (d, J=6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=172.9, 139.0, 134.4, 132.7, 130.9, 129.7, 128.6 (2C), 127.6,
127.2, 125.7 (2C), 119.5, 118.2, 99.9, 53.1, 51.4, 43.1, 29.6, 25.8, 21.7,
4-Ethyl-2,3-dihydro-1-tert-butoxycarbonyl indole (27): tert-Butyl-7-
bromo-4-ethylindoline-1-carboxylate (19 mg, 0.058 mmol) was placed in
14.4 ppm; IR (film): n˜max =2963, 2930, 2874, 1734, 1501, 1455, 1168 cmꢀ1
;
LRMS: m/z (%): 335 (21) [M+ ], 262 (48), 246 (8), 234 (14), 154 (10), 91
C
Chem. Eur. J. 2012, 18, 16890 – 16901
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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16897

L. F. Silva, Jr. et al.
(100), 65 (26); HRMS (ESI): m/z calcd for [C22H25NO2+H]+: 336.1964;
found: 336.1958.
anhydrous THF (1.5 mL) in a Schlenk flask and the solution was cooled
to 08C. A
1.62 molLꢀ1 solution of nBuLi in hexanes (0.52 mL,
0.838 mmol, 2.4 equiv) was then added dropwise, whereupon the original-
ly colorless solution turned yellow. After stirring for 30 min, this solution
was added over a period of 20 min to a solution of ester 34 (117 mg,
0.349 mmol) in anhydrous THF (1.5 mL) containing CH2Br2 (0.061 mL,
0.873 mmol, 2.5 equiv) cooled to ꢀ788C. The mixture was stirred for 1 h
and then poured into 1.2 molLꢀ1 aqueous HCl solution. The resulting
mixture was extracted with EtOAc and the organic layer was washed
with saturated aqueous NaHCO3 solution, H2O, and brine, and dried
over anhydrous MgSO4. The solvent was evaporated under reduced pres-
sure and the crude product was purified by flash chromatography (hex-
anes/EtOAc, 10:1) to afford 40 (103 mg, 0.216 mmol, 62%) as a yellow
oil and recovered starting material (25 mg, 0.075 mmol, 21%). The reac-
tion yield was 79% when considering only the reacted starting material.
1H NMR (300 MHz, CDCl3): d=7.29–7.17 (m, 3H), 7.12 (d, J=3.0 Hz,
1H), 6.98 (d, J=7.5 Hz, 1H), 6.95–6.20 (m, 3H), 6.62 (d, J=3.0 Hz, 1H),
5.68 (d, J=17.4 Hz, 1H), 5.54 (s, 1H), 5.55 (d, J=17.4 Hz, 1H), 3.91
(qdd, J=6.9, 5.1, 2.1 Hz, 1H), 3.14 (dd, J=17.7, 9.3 Hz, 1H), 3.49 (dd,
J=17.7, 9.3 Hz, 1H), 2.93 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.8 Hz, 3H),
1.06 ppm (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=195.5,
138.8, 134.7, 132.5, 131.2, 129.9, 128.8 (2C), 127.3, 127.2, 125.6 (2C),
119.8, 118.3, 100.0, 53.3, 44.1, 43.0, 28.7, 25.8, 21.4, 14.5 ppm; IR (film):
n˜max =2964, 2930, 1724, 1503, 1454 cmꢀ1; LRMS: m/z (%): 303 (100) [M+
(S)-3-(1-Benzyl-4-ethyl-1H-indol-7-yl)butanoic acid ((S)-35): The lipase
Amano PS-IM (220 mg) and H2O (0.047 mL, 2.628 mmol, 4 equiv) were
added to a stirred solution of the starting ester 34 (220 mg, 0.657 mmol)
in diisopropyl ether (DIPE, 13 mL). The mixture was heated to 408C and
stirred for 65 h. Anhydrous MgSO4 was then added, and the resulting
mixture was filtered to remove the drying agent and the enzyme from
the organic layer. The solvent was evaporated under vacuum and the
crude product was purified by flash chromatography (hexanes/EtOAc,
9:1!8:2!7:3) to afford the compound (S)-35 (44 mg, 0.138 mmol, 21%,
ee=99%) and the remaining starting ester (153 mg, 0.456 mmol, 70%),
both as yellow oils. The recovered ester was redeployed in one more
cycle, affording after the second cycle the acid (S)-35 in 32% yield with
99% ee and the recovered ester in 52% yield with 41% ee. [a]2D5 =ꢀ14.18
(c=0.005 gcmꢀ3 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.22–7.17
(m, 3H), 7.10 (d, J=3.3 Hz, 1H), 6.98–6.92 (m, 4H), 6.62 (d, J=3.3 Hz,
1H), 5.72 (d, J=17.4 Hz, 1H), 5.52 (d, J=17.4 Hz, 1H), 3.88–3.76 (m,
1H), 2.93 (q, J=7.8 Hz, 2H), 2.65 (dd, J=15.5, 5.4 Hz, 1H), 2.48 (dd, J=
15.9, 9.0 Hz, 1H), 1.36 (t, J=7.8 Hz, 3H), 1.08 ppm (d, J=6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=178.5, 138.9, 134.5, 132.7, 131.0, 129.8,
128.7 (2C), 127.4, 127.3, 125.7 (2C), 119.5, 118.3, 100.0, 53.2, 42.9, 29.5,
25.8, 21.9, 14.4 ppm; IR (film): n˜max =3028, 2964, 2928, 2872, 1706, 1501,
1454 cmꢀ1; LRMS: m/z (%): 321 (20) [M+ ], 307 (2), 262 (38), 246 (5),
C
C
ꢀ172], 288 (60), 226 (30), 210 (13), 114 (17), 91 (53); HRMS (ESI): m/z
234 (7), 170 (5), 154 (11), 91 (100); HRMS (ESI): m/z calcd for
calcd for [C22H24Br2NO+Na]+: 498.0044; found: 498.0035.
[C21H23NO2+H]+: 322.1807; found: 322.1815.
(S)-4-(1-Benzyl-4-ethyl-1H-indol-7-yl)pentanoic acid ((S)-42): A stirred
solution of (S)-35 (138 mg, 0.430 mmol) in anhydrous Et2O (6.5 mL) was
cooled to 08C. BH3·SMe2 (0.082 mL, 0.860 mmol, 2 equiv) was then
added dropwise, the mixture was allowed to warm to RT, and it was then
heated at reflux for 5 h. It was then cooled to 08C once more and
quenched by slowly adding H2O. The aqueous phase was extracted with
EtOAc, and the organic layer was washed with brine and dried over an-
hydrous MgSO4. The solvent was evaporated under vacuum and the
crude product was purified by flash chromatography (hexanes/EtOAc,
8:2!7:3) to afford the corresponding alcohol (S)-3-(1-benzyl-4-ethyl-1H-
indol-7-yl)butan-1-ol (127 mg, 0.413 mmol, 96%) as a colorless oil. This
reaction proceeded equally well when THF was used instead of Et2O and
the reflux step was replaced by a longer reaction time (>12 h) at RT,
giving the product in comparable yield. [a]2D5 =ꢀ10.48 (c=0.005 gcmꢀ3 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.30–7.19 (m, 3H), 7.08 (d, J=
3.3 Hz, 1H), 6.99–6.90 (m, 4H), 6.62 (d, J=3.3 Hz, 1H), 5.67 (d, J=
17.4 Hz, 1H), 5.50 (d, J=17.4 Hz, 1H), 3.43–3.25 (m, 3H), 2.94 (q, J=
7.5 Hz, 2H), 1.95–1.83 (m, 1H), 1.78–1.67 (m, 1H), 1.37 (t, J=7.5 Hz,
3H), 1.09 ppm (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=139.4,
134.0, 133.3, 130.8, 129.6, 128.8 (2C), 128.5, 127.3, 125.4 (2C), 119.6,
(E)-Ethyl 3-(4-ethyl-1H-indol-7-yl)but-2-enoate (36): Bromoindole
(66 mg, 0.295 mmol) was placed in a Schlenk flask under N2 atmosphere
and anhydrous MeCN (1.2 mL) was added, followed by ethyl crotonate
2
(0.58 mL, 4.72 mmol, 16 equiv), PdCl2 (5 mg, 0.029 mmol, 0.1 equiv), PACTHNUTRGENUG(N o-
tolyl)3 (18 mg, 0.059 mmol, 0.2 equiv), and Et3N (0.06 mL). The mixture
was heated to 1108C and stirred for 14 h. Brine (2 mL) was then added,
the aqueous layer was extracted with EtOAc, and the organic phase was
washed with H2O and brine and dried over anhydrous MgSO4. The sol-
vent was evaporated under reduced pressure and the crude product was
purified by flash chromatography (hexanes/EtOAc, 10:1!9:1) to afford
36 (52 mg, 0.202 mmol, 82%) as
a
brown oil. 1H NMR (300 MHz,
CDCl3): d=8.49 (brs, 1H), 7.24 (d, J=3.0 Hz, 1H), 7.15 (d, J=7.5 Hz,
1H), 6.98 (d, J=7.5 Hz, 1H), 6.63 (dd, J=3.3, 2.1 Hz, 1H), 6.23 (d, J=
1.5 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.94 (q, J=7.5 Hz, 2H), 2.67 (d, J=
1.5 Hz, 3H), 1.36 (t, J=7.4 Hz, 3H), 1.33 ppm (t, J=7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=166.9, 155.2, 137.6, 132.4, 127.6, 124.5,
123.9, 121.1, 118.3, 117.4, 59.9, 26.3, 19.7, 14.6, 14.4 ppm; IR (film): n˜max
=
3371, 2965, 2932, 1621 cmꢀ1; LRMS: m/z (%): 257 (26) [M+ ], 240 (3),
212 (100), 196 (52), 184 (7), 167 (20), 154 (15); HRMS (ESI): m/z calcd
for [C16H19NO2+Na]+: 280.1313; found: 280.1314.
C
118.4, 100.0, 60.9, 53.1, 40.6, 29.0, 25.8, 23.1, 14.5 ppm; IR (film): n˜max
=
9-Ethyl-6-methyl-5,6-dihydro-4H-pyrrolo
G
(37):
3384, 2963, 2929, 2871, 1502, 1553 cmꢀ1; LRMS: m/z (%): 307 (62) [M+ ],
292 (6), 262 (83), 234 (40), 91 (100); HRMS (ESI): m/z calcd for
[C21H25NO+H]+: 308.2014; found: 308.2013. Anhydrous CH2Cl2 was
added to a flask containing (S)-3-(1-benzyl-4-ethyl-1H-indol-7-yl)butan-
1-ol (127 mg, 0.413 mmol) followed by pyridine (0.12 mL) and a catalytic
amount of DMAP. Mesyl chloride (0.070 mL, 0.909 mmol, 2.2 equiv) was
then added dropwise, whereupon the mixture became opaque. After stir-
ring for 13 h at RT, H2O was added and the resulting mixture was ex-
tracted with CH2Cl2. The organic layer was washed with H2O/EtOH
(10:1) and brine/EtOH (10:1) and dried over anhydrous MgSO4. The sol-
vent was evaporated under reduced pressure and the crude product was
purified by flash chromatography (hexanes/EtOAc, 8:2!7:3) to afford
the mesylated product (S)-3-(1-benzyl-4-ethyl-1H-indol-7-yl)butyl metha-
C
Anhydrous methanol (7 mL) was added to a flask previously loaded with
36 (104 mg, 0.405 mmol), followed by Mg0 (97 mg, 4.05 mmol, 10 equiv).
The reaction mixture was heated at reflux for 5 h, whereupon it had
become milky white in appearance. It was then cooled to RT, 10% HCl
solution was added until acidic pH, and the aqueous layer was extracted
with EtOAc. The organic phase was washed with H2O and brine and
dried over anhydrous MgSO4. The solvent was evaporated under reduced
pressure and the crude product was purified by flash chromatography
(hexanes/EtOAc, 10:1!9:1!8:2) to afford 37 (24 mg, 0.104 mmol, 26%)
as a light-yellow oil. 1H NMR (500 MHz, CDCl3): d=7.66 (d, J=3.5 Hz,
1H), 7.10 (dd, J=7.5, 0.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.74 (d, J=
3.5 Hz, 1H), 3.46–3.32 (m, 1H), 3.02 (dd, J=17.0, 6.3 Hz, 1H), 2.87 (q,
J=7.7 Hz, 2H), 2.72 (dd, J=17.0, 8.5 Hz, 1H), 1.43 (d, J=7.0 Hz, 3H),
1.33 ppm (t, J=7.7 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=166.7,
135.6, 134.5, 127.1, 123.1, 122.4, 120.9, 120.2, 108.6, 41.0, 30.4, 26.0, 19.9,
nesulfonate (150 mg, 0.390 mmol, 94%) as a light-yellow oil. [a]D25
=
ꢀ15.78 (c=0.005 gcmꢀ3 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
7.31–7.20 (m, 3H), 7.10 (d, J=3.3 Hz, 1H), 6.94–6.90 (m, 4H), 6.62 (d,
J=3.3 Hz, 1H), 5.64 (d, J=17.4 Hz, 1H), 5.48 (d, J=17.4 Hz, 1H), 4.02–
3.94 (m, 1H), 3.72–3.65 (m, 1H), 3.48–3.36 (m, 1H), 2.93 (q, J=7.5 Hz,
2H), 2.66 (s, 3H), 2.12–1.90 (m, 1H), 1.36 (t, J=7.5 Hz, 3H), 1.02 ppm
(d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=138.9, 134.4, 133.1,
131.0, 129.8, 128.8 (2C), 127.4, 127.0, 125.6 (2C), 119.4, 118.5, 100.0, 68.9,
53.3, 37.0, 36.6, 29.0, 25.8, 22.8, 14.5 ppm; IR (film): n˜max =3029, 2963,
15.1 ppm; IR (film): n˜max =2963, 2918, 2850, 1716, 1421, 1303 cmꢀ1
;
LRMS: m/z (%): 213 (59) [M+ ], 198 (100), 182 (16), 170 (17), 153 (18),
77 (15); HRMS (ESI): m/z calcd for [C14H15NO+H]+: 214.1232; found:
214.1213.
C
4-(1-Benzyl-4-ethyl-1H-indol-7-yl)-1,1-dibromopentan-2-one (40): Tetra-
methylpiperidine (TMP; 0.16 mL, 0.942 mmol, 2.7 equiv) was dissolved in
16898
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16890 – 16901

Trikentrin Synthesis
FULL PAPER
2928, 2872, 2850, 1355, 1175 cmꢀ1; LRMS: m/z (%): 385 (42) [M+ ], 289
(15), 274 (13), 262 (58), 167 (15), 91 (100); HRMS (ESI): m/z calcd for
[C22H27NO3S+H]+: 386.1790; found: 386.1799. DMSO (1 mL) was added
to a flask containing (S)-3-(1-benzyl-4-ethyl-1H-indol-7-yl)butyl methane-
sulfonate (71 mg, 0.185 mmol), followed by KCN (24 mg, 0.370 mmol,
2 equiv). The mixture was heated to 608C and stirred for 10 h, and then
the reaction was quenched with H2O. The resulting mixture was extracted
with EtOAc, and the organic layer was washed with H2O and brine and
dried over anhydrous MgSO4. The solvent was evaporated under reduced
pressure and the remaining crude product was purified by flash chroma-
tography (hexanes/EtOAc, 8:2) to afford (S)-4-(1-benzyl-4-ethyl-1H-
indol-7-yl)pentanenitrile (48 mg, 0.152 mmol, 82%) as a colorless oil.
[a]D25 =ꢀ5.58 (c=0.005 gcmꢀ3 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.31–7.21 (m, 3H), 7.12 (d, J=3.3 Hz, 1H), 6.95–6.87 (m, 4H), 6.63
(d, J=3.3 Hz, 1H), 5.54 (d, J=17.4 Hz, 1H), 5.48 (d, J=17.4 Hz, 1H),
3.37–3.25 (m, 1H), 2.93 (q, J=7.5 Hz, 2H), 2.01–1.91 (m, 2H), 1.86–1.75
(m, 1H), 1.67–1.58 (m, 1H), 1.37 (t, J=7.5 Hz, 3H), 1.02 ppm (d, J=
6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=138.9, 134.6, 133.2, 130.0,
128.9 (2C), 127.5, 126.3, 125.5 (2C), 120.1, 119.1, 118.6, 100.0, 53.4, 33.3,
21.1, 25.8, 23.0, 15.0, 14.4 ppm; IR (film): n˜max =3029, 2964, 2930, 2871,
(S)-4-Ethyl-8,9-dihydro-9-methyl-1H-benzo[g]indol-6(7H)-one ((S)-44):
AlCl3 (168 mg, 1.266 mmol, 6 equiv) was added to a solution of 43
(67 mg, 0.211 mmol) in anisole (2.5 mL), whereupon the mixture immedi-
ately turned dark green. It was stirred for 3 h at 1008C, then cooled, and
slowly transferred to an extraction funnel containing 10% aqueous HCl
solution. The aqueous phase was extracted with EtOAc and the organic
layer was washed with brine and dried over anhydrous MgSO4. After
evaporation of the solvent under vacuum, the crude product was purified
by flash chromatography (hexanes/EtOAc, 9:1!8:2!7:3). The purified
material was dissolved in HPLC grade MeCN (10 mgmLꢀ1), injected in
0.5 mL portions into a reversed-phase preparative HPLC setup (see the
Supporting Information for details), and eluted with MeCN/H2O (6:4) as
the mobile phase to remove the benzyl migration products.[6a] The appro-
priate fractions were collected and extracted with EtOAc, and the organ-
ic layer was washed with brine and dried over anhydrous MgSO4. The
solvent was evaporated under reduced pressure to afford (S)-44 (19 mg,
0.082 mmol, 39%) as a dark-brown oil. 1H NMR (500 MHz, CDCl3): d=
8.51 (brs, 1H), 7.68 (s, 1H), 7.41 (dd, J=3.0, 2.5 Hz, 1H), 6.66 (dd, J=
3.0, 2.0 Hz, 1H), 3.46–3.40 (m, 1H), 2.95–2.90 (m, 2H), 2.89–2.84 (m,
1H), 2.64 (ddd, J=17.5, 4.5, 3.0 Hz, 1H), 2.42 (tt, J=13.5, 5.0 Hz, 1H),
2.08 (ddt, J=13.5, 5.0, 2.5 Hz, 1H), 1.48 (d, J=7.5 Hz, 3H), 1.35 ppm (t,
J=7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=198.1, 134.8, 132.8,
131.5, 131.2, 127.1, 125.7, 116.6, 102.4, 33.5, 29.5, 28.1, 26.1, 18.6,
C
2246, 1502, 1454 cmꢀ1; LRMS: m/z (%): 316 (23) [M+ ], 301 (3), 262 (21),
C
172 (9), 91 (100); HRMS (ESI): m/z calcd for [C22H24N2+H]+: 317.2018;
found: 317.2015. A 20% aqueous solution (w/w) of KOH (7 mL) was
added to a stirred solution of (S)-4-(1-benzyl-4-ethyl-1H-indol-7-yl)penta-
nenitrile (141 mg, 0.447 mmol) in ethylene glycol (7 mL), and the mixture
was heated to 1108C. After 12 h, the reaction mixture was cooled and
slowly transferred to an extraction funnel containing 10% aqueous HCl
solution. The aqueous phase was extracted with EtOAc and the organic
layer was washed with H2O followed by saturated aqueous NaHCO3 sol-
ution, then dried over anhydrous MgSO4. The solvent was evaporated
under vacuum and the crude product was purified by flash chromatogra-
phy (hexanes/EtOAc, 7:3!6:4!2:1) to furnish (S)-42 (148 mg,
0.442 mmol, 98%) as a light-brown oil. Comparable yields could be ob-
tained in shorter reaction times (<5 h) when the temperature was raised
to 1608C. [a]2D5 =ꢀ17.78 (c=0.005 gcmꢀ3 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.28–7.18 (m, 3H), 7.08 (d, J=3.2 Hz, 1H), 6.97–6.87 (m,
4H), 6.62 (d, J=3.2 Hz, 1H), 5.55 (d, J=17.3 Hz, 1H), 5.47 (d, J=
17.3 Hz, 1H), 3.29–3.18 (m, 1H), 2.93 (q, J=7.7 Hz, 2H), 2.07–1.91 (m,
2H), 1.87–1.73 (m, 2H), 1.37 (t, J=7.7 Hz, 3H), 1.09 ppm (d, J=6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=178.7, 139.1, 134.1, 133.4, 130.8,
129.7, 128.9 (2C), 127.8, 127.4, 125.5 (2C), 119.4, 118.5, 100.1, 53.3, 32.3,
32.1, 31.7, 25.8, 23.1, 14.5 ppm; IR (film): n˜max =3786, 3710, 2964, 2930,
14.5 ppm; IR (film): n˜max =3311, 2965, 2930, 2871, 1658, 1603 cmꢀ1
;
LRMS: m/z (%): 227 (97) [M+ ], 212 (100), 199 (10), 184 (36), 168 (17),
156 (52); HRMS (ESI): m/z calcd for [C15H17NO+H]+: 228.1388; found:
228.1379.
C
(S)-tert-Butyl 4-ethyl-6,7,8,9-tetrahydro-9-methyl-6-oxobenzo[g]indole-1-
carboxylate ((S)-45): Anhydrous CH2Cl2 (1 mL) was added to a Schlenk
flask containing the starting ketone (S)-44 (19 mg, 0.083 mmol) followed
by
a catalytic amount of DMAP and Boc2O (54 mg, 0.249 mmol,
3 equiv). The reaction mixture was stirred for 3 h and then H2O was
added. The resulting mixture was extracted with CH2Cl2 and the organic
layer was washed with H2O and brine and dried over anhydrous MgSO4.
The solvent was evaporated under reduced pressure and the remaining
crude product was purified by flash chromatography (hexanes/EtOAc,
10:1) to afford (S)-45 (26 mg, 0.080 mmol, 96%) as a colorless oil. [a]D25
=
+2008 (c=0.005 gcmꢀ3 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.88
(s, 1H), 7.67 (d, J=3.7 Hz, 1H), 6.64 (d, J=3.7 Hz, 1H), 4.23 (tdd, J=
7.0, 6.5, 5.5 Hz, 1H), 2.87 (q, J=7.5 Hz, 2H), 2.78 (ddd, J=16.5, 4.5,
4.5 Hz, 1H), 2.64 (dddd, J=16.5, 4.5, 4.5, 4.5 Hz, 1H), 2.41–2.35 (m, 1H),
1.94–1.88 (m, 1H), 1.66 (s, 9H), 1.32 (t, J=7.5 Hz, 3H), 1.22 ppm (d, J=
6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=199.1, 149.4, 135.7, 135.6,
134.5, 132.8, 131.4, 129.4, 121.2, 105.6, 84.1, 34.9, 29.4, 28.0, 27.7, 25.6,
2872, 2576, 1707, 1502, 1453 cmꢀ1; LRMS: m/z (%): 335 (50) [M+ ], 262
C
(81), 234 (12), 156 (14), 91 (100); HRMS (ESI): m/z calcd for
[C22H25NO2+H]+: 336.1964; found: 336.1959.
20.5, 14.7 ppm; IR (film): n˜max =2967, 2933, 2872, 1747, 1679 cmꢀ1
;
LRMS: m/z (%): 227 (93) ([M+ ꢀ100]), 212 (100), 184 (37), 156 (54);
HRMS (ESI): m/z calcd for [C20H25NO3+Na]+: 350.1732; found:
350.1727.
C
(S)-1-Benzyl-4-ethyl-8,9-dihydro-9-methyl-1H-benzo[g]indol-6(7H)-one
((S)-43):
A
nitrogen-purged flask containing acid (S)-42 (55 mg,
solution of TFA (0.134 mL,
0.164 mmol) was cooled to 08C.
A
1.806 mmol, 11 equiv) and TFAA (0.843 mL, 6.068 mmol, 37 equiv) was
then added dropwise under stirring, turning the light-brown starting ma-
terial into a dark-purple slurry. After 5 min, a saturated solution of
Na2CO3 was slowly added until the dark color of the mixture disap-
peared. The aqueous layer was extracted with EtOAc and the organic
phase was washed with brine and dried over anhydrous MgSO4. The sol-
vent was evaporated under reduced pressure and the resulting crude
product was purified by flash chromatography (hexanes/EtOAc, 10:1!
9:1!85:5!8:2) to afford (S)-43 (27 mg, 0.085 mmol, 52%) as a light-
yellow oil. [a]2D5 = +201.88 (c=0.005 gcmꢀ3 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.74 (s, 1H), 7.32–7.23 (m, 4H), 6.91–6.88 (m,
2H), 6.65 (d, J=3.3 Hz, 1H), 5.66 (d, J=17.1 Hz, 1H), 5.53 (d, J=
17.1 Hz, 1H), 3.58–3.49 (m, 1H), 2.97–2.88 (m, 2H), 2.85–2.77 (m, 1H),
2.55 (ddd, J=18.0, 5.1, 2.1 Hz, 1H), 2.12 (tt, J=13.8 Hz, 4.8 Hz, 1H),
1.88 (ddt, J=10.2, 5.7, 2.4 Hz, 1H), 1.39 (d, J=7.2 Hz, 3H), 1.37 ppm (t,
J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=198.2, 138.7, 134.6,
134.1, 133.7, 132.1, 129.0 (2C), 127.6, 126.6, 125.3 (2C), 117.4, 101.2, 52.9,
33.0, 29.1, 27.2, 25.8, 20.9, 14.3 ppm; IR (film): n˜max =3473, 3031, 2964,
(S)-tert-Butyl 4-ethyl-8,9-dihydro-9-methylbenzo[g]indole-1-carboxylate
((S)-46): NaBH4 (5 mg, 0.135 mmol, 2 equiv) was added to a solution of
(S)-45 (22 mg, 0.067 mmol) in MeOH (1 mL) at 08C. The mixture was al-
lowed to warm to RT and cold H2O was added after 30 min. The aqueous
layer was extracted with EtOAc and the organic phase was washed with
brine and dried over anhydrous MgSO4. The solvent was evaporated
under vacuum, the crude residue was redissolved in anhydrous DMF
(1.5 mL), and 85% H3PO4 (0.161 mL, 2.765 mmol, 41 equiv) was added.
The reaction mixture was then heated to 808C and stirred for 3.5 h. The
temperature was then raised to 1008C and stirring was continued for an
additional 1 h. After cooling to RT, water was added and the resulting
mixture was extracted with EtOAc. The organic layer was washed with
saturated aqueous NaHCO3 solution and brine and dried over anhydrous
MgSO4. The solvent was evaporated under reduced pressure and the
crude product was purified by flash chromatography (hexanes/EtOAc,
10:1!9:1) to afford (S)-46 (16 mg, 0.051 mmol, 76%) as a colorless oil.
[a]D25 = +96.08 (c=0.005 gcmꢀ3 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.51 (d, J=3.9 Hz, 1H), 7.83 (s, 1H), 6.56 (d, J=3.6 Hz, 1H), 6.51
(dd, J=9.6, 3.0 Hz, 1H), 5.85 (ddd, J=8.9, 2.4Hz, 6.6 Hz, 1H), 4.14 (dq,
J=6.9, 6.9 Hz, 1H), 2.82 (dq, J=7.5, 1.5 Hz, 2H), 2.67 (ddt, J=17.4, 6.9,
3.0 Hz, 1H), 2.21 (ddd, J=17.4, 6.3, 1.5 Hz, 1H), 1.63 (s, 9H), 1.29 (t, J=
2930, 2870, 1664, 1497, 1453 cmꢀ1; LRMS: m/z (%): 317 (39) [M+ ], 302
C
(26), 274 (5), 91 (100); HRMS (ESI): m/z calcd for [C22H23NO+H]+:
318.1858; found: 318.1852.
Chem. Eur. J. 2012, 18, 16890 – 16901
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16899

L. F. Silva, Jr. et al.
7.5 Hz, 3H), 1.07 ppm (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=149.9, 133.8, 133.2, 130.7, 130.1, 128.6, 128.2, 125.7, 124.5, 122.4, 105.4,
83.2, 30.8, 28.1 (3C), 27.0, 25.6, 20.0, 14.8 ppm; IR (film): n˜max =3034,
2962, 2924, 2852, 1746, 1458, 1137 cmꢀ1; LRMS: m/z (%): 211 (79) [M+
(%): 171 (35) [M+ ], 156 (100), 129 (21), 77 (29); HRMS (ESI): m/z
calcd for [C12H13N+H]+: 172.1126; found: 172.1119.
C
7-Ethyl-3H-pyrroloACTHNUTRGNEUNG
[3,2,1-ij]quinolin-3-one (55): A 0.5 molLꢀ1 aqueous
NaOH solution (0.18 mmol) was added to ester 36 (38 mg, 0.16 mmol)
and the mixture was stirred for 10 h at RT. H2O was then added to
quench the reaction and the resulting mixture was extracted with EtOAc.
The organic layer was washed with brine and dried over anhydrous
MgSO4, and the solvent was evaporated under vacuum. The crude prod-
uct was purified by flash chromatography (hexanes/EtOAc, 7:3) to afford
55 (10 mg, 0.051 mmol, 32%) as a colorless oil. 1H NMR (200 MHz,
CDCl3): d=7.93 (d, J=3.8 Hz, 1H), 7.79 (d, J=9.4 Hz, 1H), 7.52 (d, J=
7.9 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.92 (d, J=3.8 Hz, 1H), 6.64 (d, J=
9.4 Hz, 1H), 3.00 (q, J=7.7 Hz, 2H), 1.35 ppm (t, J=7.7 Hz, 3H);
13C NMR (50 MHz, CDCl3): d=159.7, 143.4, 138.8 (2C), 126.7, 124.8,
123.7, 123.0, 122.3, 115.2, 109.3, 26.7, 15.6 ppm; IR (film): n˜max =2964,
C
ꢀ100], 196 (100), 180 (28), 167 (82), 152 (10), 90 (25); HRMS (ESI): m/z
calcd for [C20H25NO2+Na]+: 334.1783; found: 334.1779.
ACHTUNGTRENNUNG
A
(40 mg, 0.129 mmol) in anhydrous MeCN (3 mL) was placed in a Schlenk
flask filled with N2 and cooled to ꢀ408C. TTN (63 mg, 0.141 mmol,
1.1 equiv) was added, the mixture was stirred for 5 min, and then NaBH4
(20 mg, 0.529 mmol, 4.1 equiv) was added. The temperature was allowed
to reach ꢀ208C (20 min) and the reaction was quenched by adding H2O.
The aqueous layer was extracted with EtOAc and the organic phase was
washed with saturated aqueous NH4Cl solution, H2O, and brine, and
dried over anhydrous MgSO4. The solvent was evaporated under vacuum
and the crude product was purified by flash chromatography (hexanes/
EtOAc, 10:1!9:1!85:5!8:2) to afford 47 (21 mg, 0.064 mmol, 50%) as
a colorless oil and recovered starting material (9 mg, 0.029 mmol, 22%).
Considering only the reacted material, the reaction yield was 64%.
[a]D25 = +116.88 (c=0.005 gcmꢀ3 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=7.50 (d, J=3.7 Hz, 1H), 7.02 (s, 1H), 6.60 (d, J=3.7 Hz, 1H), 4.23
(tdd, J=11.0, 9.5, 3.0 Hz, 1H), 3.89 (ddd, J=16.0, 10.5, 5.0 Hz, 2H), 3.54
(dq, J=7.5, 2.0 Hz, 1H), 2.88 (q, J=7.5 Hz, 2H), 2.21 (dt, J=12.5,
8.0 Hz, 1H), 1.99 (ddd, J=12.5, 8.0, 3.0 Hz, 1H), 1.63 (s, 9H), 1.30 (t, J=
7.5 Hz, 3H), 1.13 ppm (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d=149.1, 140.4, 135.1, 133.2, 131.8, 129.9, 126.3, 117.9, 105.7, 83.1, 66.6,
46.1, 36.7, 36.9, 28.1 (3C), 26.0, 22.0, 15.1 ppm; IR (film): n˜max =3420,
2965, 2928, 2867, 1746, 1336, 1139 cmꢀ1; LRMS: m/z (%): 229(20) [M+
2918, 1849, 1679, 1629, 1607 cmꢀ1; LRMS; m/z (%): 197 (47) [M+ ], 182
C
(100).
(+)-trans-Trikentrin A: The starting alcohol 47 (9 mg, 0.027 mmol) was
dissolved in CH2Cl2 (1.5 mL), and Et3N (0.243 mL, 1.743 mmol, 64 equiv)
and TsCl (10 mg, 0.054 mmol, 2 equiv) were added. After about 3 h, the
originally colorless mixture turned yellow. After stirring for 18 h at RT,
H2O was added and the resulting mixture was extracted with CH2Cl2.
The organic layer was washed with brine/EtOH (10:1) and dried over an-
hydrous MgSO4. The solvent was evaporated under reduced pressure and
the remaining crude product was purified by flash chromatography (hex-
anes/EtOAc, 10:1!9:1!8:2!7:3) to afford the corresponding tosylated
compound as a colorless oil. This material was dissolved in DMSO
(2 mL) and NaBH4 (6 mg, 0.162 mmol, 6 equiv) was added. The reaction
mixture was heated to 1108C and turned from colorless to yellow after a
few hours. After stirring for 43 h, H2O was added and the aqueous phase
was extracted with EtOAc. The organic layer was washed with saturated
aqueous NH4Cl solution and brine and dried over anhydrous MgSO4.
The solvent was evaporated under reduced pressure and the crude mate-
rial was purified by flash chromatography (hexanes/EtOAc, 10:1!9:1) to
afford (+)-trans-trikentrin A[6a] (4 mg, 0.019 mmol, 70% over two steps)
as a brown oil. [a]D25 = +248 (c=0.00125 gcmꢀ3 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.02 (brs, 1H), 7.16 (dd, J=2.9, 2.6 Hz, 1H), 6.83
(s, 1H), 6.59 (dd, J=3.3, 2.0 Hz, 1H), 3.58–3.48 (m, 1H), 3.41 (ddq, J=
7.2, 7.2, 6.9 Hz, 1H), 2.95 (q, J=7.5 Hz, 2H), 2.09–1.91 (m, 2H), 1.36 (t,
J=7.5 Hz, 3H), 1.33 (d, J=6.9 Hz, 3H), 1.30 ppm (d, J=6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=142.5, 135.1, 132.1, 127.2, 126.1, 122.8,
C
ꢀ100], 198 (100), 182 (18), 168 (64), 154 (35); HRMS (ESI): m/z calcd
for [C20H27NO3+Na]+: 352.1889; found: 352.1886.
1,6,7,8-Tetrahydro-6-methylcyclopenta[g]indole (54):
A
solution of
alkene 51[26] (50 mg, 0.186 mmol) in anhydrous MeCN (3 mL) was placed
in a Schlenk flask filled with N2 and cooled to ꢀ408C. TTN (91 mg,
0.205 mmol, 1.1 equiv) was added, the mixture was stirred for 5 min, and
then NaBH4 (29 mg, 0.763 mmol, 4.1 equiv) was added. The temperature
was allowed to reach ꢀ208C (20 min) and the reaction was quenched by
adding H2O. The aqueous layer was extracted with EtOAc and the organ-
ic phase was washed with saturated aqueous NH4Cl solution and brine,
and dried over anhydrous MgSO4. The solvent was evaporated under
vacuum and the crude product was purified by flash chromatography
(hexanes/EtOAc, 10:1!9:1!8:2) to afford alcohol 52 (27 mg,
0.094 mmol, 51%) as a colorless oil. The alcohol 52 (17 mg, 0.059 mmol)
was dissolved in CH2Cl2 (3.2 mL), and then Et3N (0.5 mL) and TsCl
(23 mg, 0.118 mmol, 2 equiv) were added. After about 3 h, the originally
colorless mixture turned yellow. After stirring for 18 h at RT, H2O was
added and the resulting mixture was extracted with CH2Cl2. The organic
layer was washed with brine/EtOH (10:1) and dried over anhydrous
MgSO4. The solvent was evaporated under reduced pressure and the re-
maining crude product was purified by flash chromatography (hexanes/
EtOAc, 10:1!9:1!8:2!7:3) to afford the corresponding tosylated com-
pound 53 as a colorless oil in quantitative yield. This reaction was repeat-
ed to accumulate enough material. The tosylated product (19 mg,
0.043 mmol) was dissolved in DMSO (2 mL) and NaBH4 (5 mg,
0.129 mmol, 3 equiv) was added. The mixture was heated to 808C and
turned from colorless to yellow after a few hours. After stirring for 17 h,
H2O was added and the aqueous phase was extracted with EtOAc. The
organic layer was washed with saturated aqueous NH4Cl solution and
brine and dried over anhydrous MgSO4. The solvent was evaporated
under reduced pressure and the crude material was purified by flash
chromatography (hexanes/EtOAc, 10:1!9:1!8:2) to afford indole 54
114.1, 101.5, 43.8, 37.9, 36.0, 26.5, 20.8, 20.0, 15.0 ppm; IR (film): n˜max
=
3415, 2960, 2925, 2667, 1260, 1094, 1026, 901 cmꢀ1; LRMS: m/z (%): 213
(46) [M+ ], 198 (100), 184 (14), 169 (29), 154 (14); HRMS (ESI): m/z
C
calcd for [C15H19N+H]+: 214.1596; found: 214.1581.
Acknowledgements
The authors wish to thank the CNPq, FAPESP, and CAPES for financial
support, and Professor L. H. Andrade (USP) and Professor R. O. M. A.
Sousa (UFRJ) for fruitful discussions and for providing the enzymes. S.
Lazar (AmanoEnzyme-USA) is acknowledged for providing a sample of
PS-IM. Dr. M. Schrems and Prof. A. Pfaltz (University of Basel) are ac-
knowledged for their help during the asymmetric hydrogenations and for
kindly providing the catalysts.
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a
light-brown oil. 1H NMR (500 MHz,
CDCl3): d=7.95 (brs, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.16 (dd, J=3.0,
3.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.56 (dd, J=3.0, 3.0 Hz, 1H), 3.35
(qdd, J=7.0, 7.0, 7.0 Hz, 1H), 3.07 (ddd, J=15.5, 9.0, 4.5 Hz, 1H), 2.94
(ddd, J=15.0, 8.0, 8.0 Hz, 1H), 2.45 (dddd, J=16.0, 8.0, 8.0, 4.0 Hz, 1H),
1.78–1.71 (m, 1H), 1.33 ppm (d, J=7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=143.1, 132.8, 126.6, 124.8, 123.4, 118.8, 115.7, 103.1, 39.7, 34.8,
28.4, 20.8 ppm; IR (film): n˜max =3411, 2954, 2924, 2865 cmꢀ1; LRMS: m/z
16900
www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16890 – 16901

Trikentrin Synthesis
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Received: July 6, 2012
Revised: September 4, 2012
Published online: November 4, 2012
Chem. Eur. J. 2012, 18, 16890 – 16901
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16901