Synthesis of azepino[4,5- b ]indolones by an intramolecular cyclization of unsaturated tryptamides

Article abstract of DOI:10.1055/s-0034-1379083

A facile general route for the synthesis of azepino[4,5-b]indolones is presented. The strategy involves a Bronsted acid assisted intramolecular cyclization of unsaturated tryptamides. The methodology developed has been applied to the synthesis of the ABCD

Full text of DOI:10.1055/s-0034-1379083

LETTER
▌2585
lSetyternthesis of Azepino[4,5-b]indolones by an Intramolecular Cyclization of
Unsaturated Tryptamides
Azepino[4,5-b]indolones
John Eugene Nidhiry, Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Sir C. V. Raman Avenue, Bangalore 560012, India
Fax +91(80)23600529; E-mail: prasad@orgchem.iisc.ernet.in
Received: 03.07.2014; Accepted after revision: 15.08.2014
Dedicated to Prof. H. Ila, an outstanding organic chemist from India, on the occasion of her 70th birthday
The first synthesis of an azepino[4,5-b]indolone, such as
a, was reported by Teuber et al. starting from dihydro-
carbazolone 5 using a Schmidt reaction. Later, structural-
Abstract: A facile general route for the synthesis of azepino[4,5-
b]indolones is presented. The strategy involves a Brønsted acid as-
sisted intramolecular cyclization of unsaturated tryptamides. The
1
9
methodology developed has been applied to the synthesis of the ly similar compounds such as 1b and 1c were synthesized
1
0
ABCD tetracyclic core of the natural product tronocarpine.
by Freter via an acid-mediated electrophilic cyclization
of phenylchloroacetyltryptamide 6 and by Glushkov et
Key words: alkaloids, azepino[4,5-b]indolone, tronocarpine, trypt-
amide, ethyl lactate
1
1
al. using a Fischer indole synthesis with α-oxocaprolac-
tam 7. Hydrogenation–lactamization of the nitro-olefin 8
derived from indolyl-2-acetate via a nitro-Mannich reac-
tion were the key steps in the synthesis of 1a, described by
The presence of structurally diverse molecular architec-
tures is a characteristic feature in naturally occurring in-
1
2
Mahboobi and Bernauer. A xanthate-mediated intramo-
1
lecular annulation of tryptamide 9 using lauroyl peroxide
dole alkaloids. The development of novel synthetic
1
3a
was reported by Zard’s group for the synthesis of 1b,
methodologies to access such frameworks is of immense
2
while an analogous intermolecular version of this reaction
was used by Martinez’s group for the synthesis of such
importance in heterocyclic chemistry. The azepino[4,5-
b]indolone unit 1a is a structural motif found in indole al-
1
3b
3
structures. Van der Eycken and co-workers have report-
ed a Pd-catalyzed intramolecular acetylene hydroaryla-
tion reaction of 2-iodotryptamide derivative 10 for the
kaloids such as tronocarpine (2), malassezindole A (3a)
4
5
and malassezindole B (3b) and lasiodipline F (4) (Figure
). The presence of a quaternary stereogenic center adja-
cent to the C-2 position of the indole ring is a common
1
14
synthesis of 1d (Scheme 1).
6
feature in these natural products. While dopamine and Although simple azepino[4,5-b]indolones can be ac-
7
opioid receptor binding abilities have been attributed to cessed by the aforementioned methods, approaches to the
synthetic derivatives containing an azepino[4,5-b]indo- synthesis of compounds such as 1b, possessing a quater-
1
3b
lone unit, the potential of such compounds to treat Alzhei- nary stereogenic center, are limited. The pharmacolog-
mer’s disease has also been reported.8
ical importance of the azepino[4,5-b]indolone framework
1
5
coupled with our interest in indole alkaloids, led us to
devise an approach involving an intramolecular cycliza-
tion of α,β-unsaturated tryptamide 11 to access com-
pounds such as 12 (Scheme 1). Herein, we disclose a
simple and general route to synthesize azepino[4,5-b]in-
dolones possessing a quaternary stereogenic center via
NH
O
NH
N
O
O
N
H
HO
1a
2
Brønsted acid mediated intramolecular S ′ reaction.
N
O
As outlined in Scheme 2, synthesis of the requisite precur-
sors 11a and 11b was accomplished from (S)-ethyl lac-
tate. DIBAL-H reduction of α-silyloxy ester 13a to the
corresponding aldehyde and further Wittig–Horner olefi-
nation with phosphorane 14 furnished the α,β-unsaturated
ester 15a in 73% yield. Hydrolysis of the ester with LiOH
afforded the corresponding silyloxy acid 16a along with
the silyl-deprotected acid. To avoid a cumbersome sepa-
ration, the mixture was converted into the silyloxy silyl
ester, which, on reaction with K CO , afforded the pure si-
OH
NH
SMe
NH
O
HN
O
N
H
R
N
O
H
N
H
3
3
a R = H
b R = OH
4
Figure 1 The azepino[4,5-b]indolone framework 1a and related nat-
ural products 2–4
2
3
lyloxy acid 16a in 83% yield. Amidation of the silyloxy
acid 16a with the corresponding tryptamine afforded
tryptamides 17a and 17b in 75% and 79% yields, respec-
tively. Treatment of the tryptamides 17a and 17b with
SYNLETT 2014, 25, 2585–2590
Advanced online publication: 02.10.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379083; Art ID: st-2014-d0562-l
Georg Thieme Verlag Stuttgart · New York
©

2586
J. E. Nidhiry, K. R. Prasad
LETTER
reported approaches for azepino[4,5-b]indolones:
ries of conditions. Initial reaction of hydroxy tryptamide
11a with TFA gave a mixture of unidentifiable com-
pounds, possibly due to interference from the free amide
NH, whereas reaction of N-allyl tryptamide 11b with TFA
did not progress at room temperature. Heating the reaction
mixture to 80 °C, furnished the corresponding azepi-
no[4,5-b]indolone 12b possessing a quaternary stereogen-
NH
O
N
NH
O
O
H
6
Cl
N
H
Ph
5
O
7
ref. 10
ref. 9
ref. 11
ic center in 17% yield via an intramolecular S ′-type
N
a: R1 = R2 = H
b: R1 ≠ R2 = H, aryl, alkyl
cyclization, thus indicating that a secondary amide was
necessary in the substrate. Considering 11b as the model
substrate, the optimization of the reaction conditions was
carried out by screening different Brønsted acids and sol-
vents. The results of this study are compiled in Table 1.
Strong Brønsted acids such as CF SO H and MeSO H did
R3
1
N
1
1
c: R1 = R2 = NNHPh, O
1d: R –R2 = CHMe
O
N
R1 R2
1
H
ref. 12
ref. 14
ref. 13a
3
3
3
NO
2
not furnish the desired product, while the use of PTSA
gave the desired product 12b in an improved 55% yield
(entries 2–4, Table 1). Employing (+)-camphorsulfonic
acid (CSA) afforded 12b in an increased 71% yield (entry
5, Table 1). The use of more equivalents of (+)-CSA (5
equiv) reduced the reaction time, while a catalytic amount
of (+)-CSA (20 mol%) decreased the reaction rate and
lowered the yield significantly (entries 6 and 7, Table 1).
When the reaction was performed in 1,2-DCE a marginal
drop in the yield was observed, while the use of acetoni-
trile as solvent gave 12b in only 36% yield (entries 9 and
10, Table 1). Additionally, we were also curious to find
out if the chirality transfer from the allylic alcohol was
O
Bn N
I
N
Me
N
O
N
H
1
0
N
H
H
S
O
R1
S
8
MeO
9
EtO
present work:
3
R3
N
R
N
O
R2
i) C3 substitution
N
H
O
N
R2
H
ii) C–C bond
migration
OH
1
1
1
2
R1
R1
H
Scheme 1 Reported approaches for the synthesis of azepino[4,5-
b]indolone framework; the current approach presented herein
Table 1 Optimization of the Reaction Conditionsa
N
N
TBAF furnished the hydroxy tryptamides 11a and 11b in
good yields.
O
N
Brønsted acid
H
O
Et
N
H
solvent
80 °C
Et
After accessing the required tryptamides 11a and 11b, the
key intramolecular cyclization was attempted under a se-
1
1b
12b
HO
2 2
i) DIBAL-H, CH Cl
Equiv Time (h) Yield (%)b
OTBS
TBSO
Et
Entry
Reagent
Solvent
–78 °C, 0.5 h
OEt
OEt
ii)
Et
1
2
3
4
5
6
7
8
9
TFA
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
DCE
2
0.5
0.5
0.5
2
17
O
O
OEt
Ph
3
P
13a
15a
0c
CF SO H
2
14
3
3
O
toluene, Δ, 8 h
3% (over 2 steps)
0c
MeSO H
2
7
3
PTSA
2
55
i) LiOH, dioxane–H
2
O, Δ, 10 h
TBSO
Et
(+)-CSA
(+)-CSA
(+)-CSA
(–)-CSA
(+)-CSA
(+)-CSA
2
2
71
65
51
63
62
36
ii) TBSCl, imidazole, CH
2
Cl
2
, r.t., 6 h
OH DCC, DMAP
tryptamines
iii) K
8
2
CO
3
, MeOH, r.t., 1 h
3% (over 3 steps)
5
1
O
2 2
CH Cl , r.t., 4 h
16a
0.2
2
24
2
N
R
N
R
O
O
N
2
2.5
1.5
N
TBAF, THF
H
H
Et
Et
0
°C to r.t., 3h
1
0
MeCN
2
a
b
c
HO
11a R = H 92%
11b R = allyl 94%
All reactions were performed at 0.1 M dilution at 80 °C.
Isolated yield after silica gel column chromatography.
The reaction was performed at 0 °C; the starting material showed
TBSO
7a R = H 75%
7b R = allyl 79%
1
1
completion by TLC. TFA = trifluoroacetic acid, PTSA = p-toluene-
sulfonic acid, CSA = camphorsulfonic acid, DCE = 1,2-dichloro-
ethane.
Scheme 2 Synthetic route for the preparation of tryptamides 11a and
1b
1
Synlett 2014, 25, 2585–2590
© Georg Thieme Verlag Stuttgart · New York

LETTER
Azepino[4,5-b]indolones
2587
complete in the formation of 12b, which consequently a free indole NH are comparatively better substrates for
would provide an insight into the reaction mechanism. undergoing an intramolecular S ′-type cyclization to fur-
N
Chiral HPLC analysis of 12b showed an enantiomeric ra- nish the corresponding azepino[4,5-b]indolones in good
tio of 60:40 (20% ee) indicating a loss of chirality in the yields.
reaction process.16 An enantiomeric excess of 20% sug-
Interestingly, the substrate 11k having extended conjuga-
tion, furnished the tetracyclic compound 12k, probably
resulting from the initial cyclization to form the azepi-
no[4,5-b]indolone followed by subsequent capture of the
more stable carbocationic intermediate by the indole ni-
gests that the reaction predominantly proceeds through an
1
7
SN1′ pathway via a carbocationic intermediate. The
structure of 12b was unambiguously confirmed by single
crystal X-ray diffraction analysis.18
To explore the scope and limitations of the reaction, the trogen (Scheme 3). The relative configurations of the
19
synthesis of precursors 11c–m (Figure 2) was accom- newly formed stereogenic centers were assigned on the
2
1
plished using a similar protocol as described in Scheme 2. basis of X-ray crystal structure analysis of 12k.
The synthesized hydroxy tryptamides 11c–j were subject-
ed to the optimized reaction conditions of two equivalents
of (+)-CSA in benzene at 80 °C, and the results are sum-
marized in Table 2. It was found that the reaction of trypt-
amides 11c–f derived from ethyl lactate 13a comprising a
methyl, benzyl and p-methoxy benzyl substituent on the
nitrogen of tryptamine, afforded the corresponding azepi-
no[4,5-b]indolones 12c–f possessing quaternary stereo-
genic centers in 60–71% yields (entries 1–4, Table 2).
Scheme 3 Formation of a tetracyclic azepino[4,5-b]indolone 12k
and an ORTEP diagram of 12k at 50% probability
Substrate 11g, possessing no substitution on the double
bond in the unsaturated tryptamide furnished the azepi-
no[4,5-b]indolone 12g resulting from migration of the
double bond to form the more stable conjugated lactam as
The N-allyl tryptamide 11l derived from methyl mande-
late furnished the azepino[4,5-b]indolone 12l in only 23%
yield along with a mixture of unidentifiable compounds.
While in case of the N-benzyl analogue 11m, it is worth
noting that the formation of an azonino[5,4-b]indolone 18
takes place in 23% yield along with the desired azepi-
no[4,5-b]indolone 12m. The formation of a stabilized π-
allyl carbocation leads to two possible modes of nucleo-
philic attack of the indole ring, viz. an S 1 pathway result-
ing in 18 and S 1′ pathway leading to 12m (Scheme 4).
Interestingly, the isomerization of the E-olefin to the Z-
olefin occurred during the course of formation of 18 as es-
tablished by the X-ray crystallographic analysis.
separable E/Z isomers in 2:3 ratio, respectively (entry 5,
Table 2).20 Tryptamide 11h derived from methyl 3-hy-
droxyvalerate gave the azepino[4,5-b]indolone 12h in
40% yield (entry 6, Table 2). The reaction of tryptamide
11i containing a primary allylic alcohol was very sluggish
(
2
24 h) and the desired product 12i was obtained in only
9% yield along with a mixture of unidentifiable com-
N
pounds (entry 7, Table 2). Substrate 11j with a protected
indole NH also delivered the desired product 12j in 47%
yield (entry 8, Table 2). Therefore, it can be inferred that
tryptamides derived from ethyl lactate possessing a sec-
ondary amide NH, a secondary allylic hydroxy group and
N
2
2
N
Me
Et
N
Bn
Et
N
PMB
Et
N
Bn
O
O
O
N
H
O
N
H
N
H
N
H
1
1
7c (76%)
1c (84%)
17d (63%)
11d (80%)
17e (55%)
11e (94%)
17f (56%)
11f (89%)
PO
N
PO
PO
PO
N
Bn
N
Bn
Et
Bn
N
Bn
Et
-Pr
O
O
O
O
N
N
N
H
N
H
H
Me
1
7g (63%)
17h (53%)
11h (83%)
i
17i (69%)
11i (72%)
17j (86%)
11j (83%)
1
1g (94%)
PO
O
PO
PO
N
PO
Bn
N
N
Bn
Et
O
17c–m P = TBS
17i P = Tr
N
O
N
N
H
H
Et
Ph
H
1
1c–m P = H
Ph
1
7k (99%)
17l (74%)
11l (63%)
17m (67%)
11m (81%)
PO
PO
1
1k (88%)
PO
Figure 2 Yields of tryptamides 17c–m and hydroxy tryptamides 11c–m
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2585–2590

2588
J. E. Nidhiry, K. R. Prasad
LETTER
Table 2 Substrate Scope of the Intramolecular Cyclizationa
N
N
Entry Substrate Azepino[4,5-b]indolone Time (h) Yield (%)b
O
(+)-CSA
benzene
N
H
Et
Ph
O
N
H
Et
8
0 °C, 0.5 h
2
3%
Me
N
1
2l
Ph
1
1l
HO
O
N
H
1
11c
Et
Et
Et
2.5
71
Bn
Bn
N
N
O
(
+)-CSA
1
1
1
2c
2d
2e
11m
O
+
N
benzene
80 °C, 0.5 h
H
Et
Et
Bn
N
N
N
N
H
Ph
Ph 18 23%
1
2m 25%
O
N
H
2
3
11d
11e
1.5
61
60
Scheme 4 An unexpected formation of azonino[5,4-b]indolone 18
ed a mixture of indolones 19 and 20 resulting from the al-
lylation of 12d at C3 and the indole NH in 47% and 28%
yields, respectively. Subsequent treatment of 20 with
Grubbs’ 2nd generation catalyst in refluxing CH Cl fur-
nished the ABCD tetracyclic core 21 of tronocarpine (2)
PMB
O
N
H
1
24
2
2
in good yield (Scheme 5).
Bn
O
Bn
N
N
H
4
5
6
11f
11g
11h
2.5
64
56
40
Bn
Br
N
O
N
1
2d
+
Et
NaH, DMF
°C, 0.5 h
N
O
Et
1
1
2f
0
Bn
N
N
19 (47%)
20 (28%)
O
N
H
3
NH
Bn
Grubbs II
catalyst (10 mol%)
N
2g
O
N
Bn
CH Cl , Δ, 10 h
O
2
2
7%
N
Et
O
7
HO
O
2
N
H
Et
3
21
i-Pr
Scheme 5 Synthesis of ABCD ring system of tronocarpine (2)
1
1
2h
2i
Bn
In another application, 12b was reduced to the corre-
N
sponding azepino[4,5-b]indole 22 with LiAlH in 60%
4
O
N
H
7
11i
11j
24
29
47
yield. Ring-closing metathesis reaction of 22 with
Grubbs’ 2nd generation catalyst furnished the tetracycle
23 in 58% yield, which forms the core of a number of in-
dole alkaloids such as ibogamine (24) and catharanthine
Bn
N
(25) (Scheme 6).
O
N
Et
In summary, a facile route to azepino[4,5-b]indolones
possessing a quaternary stereogenic center via Brønsted
acid mediated intramolecular cyclization has been devel-
oped. A comparative study was conducted to examine the
effect of various substituents in determining the outcome
of the reaction. Substrates derived from ethyl lactate
proved to be the most effective. During the course of this
study, an interesting formation of a tetracyclic azepi-
no[4,5-b]indolone 12k and also that of azonino[5,4-b]in-
dolone 18 were observed. The presence of alkyl and
alkenyl moieties in the quaternary center allowed the
functionalization of these compounds and was subse-
quently employed to access the ABCD tetracyclic core of
8
1.5
Me
1
2j
a
Reaction conditions: substrate (0.1 mmol), (+)-CSA (0.2 mmol) in
benzene (1 mL) at 80 °C.
Isolated yield after silica gel column chromatography.
b
An application of the developed methodology for the syn-
thesis of the ABCD core of the indole alkaloid trono-
carpine (2) was then considered. Accordingly, allylation
of azepino[4,5-b]indolone 12d with allyl bromide afford-
23
Synlett 2014, 25, 2585–2590
© Georg Thieme Verlag Stuttgart · New York

LETTER
Azepino[4,5-b]indolones
2589
(
7) Asche, G.; Kunz, H.; Nar, H.; Köppen, H.; Briem, H.; Pook,
K.-H.; Schiller, P. W.; Chung, N. N.; Lemieux, C.; Esser, F.
J. Peptide Res. 1998, 51, 323.
N
Grubbs II
(10 mol%)
LiAlH
Δ, 5 h
0%
4
–THF
12b
N
CH2Cl , Δ, 1 h
2
H
6
Et
58%
(8) Gordillo-Cruz, R. E.; Rentería-Gómez, A.; Islas-Jácome, A.;
Cortes-García, C. J.; Díaz-Cervantes, E.; Robles, J.; Gámez-
Montaño, R. Org. Biomol. Chem. 2013, 11, 6470.
22
(
9) Teuber, H.-J.; Cornelius, D.; Wolker, U. Liebigs Ann. Chem.
N
H
N
N
H
1966, 696, 116.
Et
Et
H
(
10) Freter, K. Liebigs Ann. Chem. 1969, 721, 101.
N
H
MeO
N
N
H
H
(11) Glushkov, R. G.; Zasosova, I. M.; Ovcharova, I. M.;
Solov’eva, N. P.; Sheinker, Y. N. Chem. Heterocycl. Compd.
(Engl. Transl.) 1979, 15, 780.
H
Et
H
H
O
ibogamine (24)
catharanthine (25)
2
3
(
12) Mahboobi, S.; Bernauer, K. Helv. Chim. Acta 1988, 71,
034.
2
Scheme 6 Synthesis of tetracyclic core of ibogamine (24) and catha-
ranthine (25)
(
13) (a) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z.
Angew. Chem. Int. Ed. 2000, 39, 731. (b) Reyes-Gutiérrez,
P. E.; Torres-Ochoa, R. O.; Martínez, R.; Miranda, L. D.
Org. Biomol. Chem. 2009, 7, 1388.
tronocarpine. Currently, efforts are underway to develop
an enantioselective version of the intramolecular cycliza-
tion and also to synthesize some of the natural products
possessing the azepino[4,5-b]indolone framework.
(
14) Peshkov, V. A.; Van Hove, S.; Donets, P. A.; Pereshivko, O.
P.; Van Hecke, K.; Van Meervelt, L.; Van der Eycken, E. V.
Eur. J. Org. Chem. 2011, 1837.
(15) (a) Prasad, K. R.; Nidhiry, J. E.; Sridharan, M. Tetrahedron
2014, 70, 4611. (b) Nidhiry, J. E.; Prasad, K. R. Tetrahedron
2013, 69, 5525. (c) Prasad, K. R.; Nidhiry, J. E. Synlett 2012,
23, 1477.
Acknowledgment
J.E.N. thanks the Council of Scientific and Industrial Research
(16) Representative Procedure for the Preparation of
Azepino[4,5-b]indolones: To a solution of hydroxy
(CSIR), New Delhi for a Research Fellowship. The authors are very
grateful to Mr. K. Durgaprasad and Prof. T. N. Guru Row of the So-
lid State and Structural Chemistry Unit, Indian Institute of Science
for their kind help in the single crystal X-ray diffraction analysis of
some of the compounds.
tryptamide 11b (33 mg, 0.10 mmol) in anhyd benzene (1
mL) under nitrogen atmosphere was added (+)-CSA (46 mg,
0.2 mmol). The resulting mixture was heated to 80 °C and
was stirred at that temperature for 2 h. After completion of
reaction (as indicated by TLC), the reaction mixture was
cooled to r.t. and quenched by the addition of sat. NaHCO3
solution to a pH value of ca. 9 and was then extracted with
EtOAc (2 × 5 mL). The combined organic layers were
washed with brine (5 mL) and dried over anhyd Na SO . The
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
1
0.1055/s-00000083.SunpfgIpi
o
nr
i
o
2
4
crude residue obtained after filtration and evaporation of the
solvent was purified by silica gel column chromatography
using petroleum ether–EtOAc (4:1) as eluent to afford
azepino[4,5-b]indolone 12b (22 mg, 71%) as a pale yellow
solid. Recrystallization of 12b from petroleum ether–EtOH
solvent system (9:1) gave crystals suitable for X-ray
References and Notes
(
1) (a) Veale, C. G. L.; Davies-Coleman, M. T. In The
Alkaloids: Chemistry and Biology; Vol. 73; Knölker, H.-J.,
Ed.; Academic Press: Amsterdam, 2014. (b) Bhat, V.; Dave,
A.; MacKay, J. A.; Rawal, V. H. In The Alkaloids:
24
diffraction analysis; mp 168–170 °C; [α]D –26.3 (c, 0.35,
CHCl ), corresponding to 20% ee as determined by chiral
Chemistry and Biology; Vol. 73; Knölker, H.-J., Ed.;
Academic Press: Amsterdam, 2014. (c) Ishikura, M.; Abe,
T.; Choshi, T.; Hibino, S. Nat. Prod. Rep. 2013, 30, 694.
3
HPLC analysis [CHIRACEL OD-H, isopropanol–hexane
(
5:95), flow rate = 1.0 mL/min, t (major) = 12.11 min, t
R
R
(
1
minor) = 28.76 min]. IR (KBr): 3387, 2919, 1625, 1464,
(d) Rahman, A. U.; Basha, A. Indole Alkaloids; Harwood
–1 1
233 cm . H NMR (400 MHz, CDCl ): δ = 7.95 (br s, 1 H),
Academic Publishers: Amsterdam, 1998.
3
7.47 (d, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.19 (t, J
(2) (a) Bauer, I.; Knölker, H.-J. Top. Curr. Chem. 2012, 309,
=
9
7.2 Hz, 1 H), 7.11 (t, J = 7.2 Hz, 1 H), 5.87 (ddt, J = 17.2,
.2, 5.6 Hz, 1 H), 5.72 (dd, J = 15.6, 1.6 Hz, 1 H), 5.27 (dq,
J = 15.6, 6.4 Hz, 1 H), 5.21 (dd, J = 16.0, 1.2 Hz, 1 H), 5.19
d, J = 9.2 Hz, 1 H), 4.28 (dd, J = 15.2, 5.6 Hz, 1 H), 4.02–
203. (b) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed.
2
009, 48, 9608. (c) Humphrey, G. R.; Kuethe, J. T. Chem.
Rev. 2006, 106, 2875. (d) Agarwal, S.; Cammerer, S.; Filali,
S.; Frohner, W.; Knoll, J.; Krahl, M. P.; Reddy, K. R.;
Knölker, H.-J. Curr. Org. Chem. 2005, 9, 1601. (e) Gribble,
G. W. Pure Appl. Chem. 2003, 75, 1417. (f) Gribble, G. W.
J. Chem. Soc., Perkin Trans. 1 2000, 1045. (g) Sapi, J.;
Massiot, G. In Monoterpenoid Indole Alkaloids, The
Chemistry of Heterocyclic Compounds; Vol. 25; Saxton,
J. E.; Taylor, E. C., Eds.; Wiley: New York, 1994.
(
4.15 (m, 2 H), 3.41 (dt, J = 15.2, 4.0 Hz, 1 H), 2.88–3.05 (m,
2
H), 2.57 (sext, J = 7.2 Hz, 1 H), 1.92 (sext, J = 7.2 Hz, 1
1
3
H), 1.67 (d, J = 6.4 Hz, 3 H), 0.97 (t, J = 7.2 Hz, 3 H).
C
NMR (100 MHz, CDCl ): δ = 171.7, 135.1, 134.8, 133.7,
3
1
1
31.8, 128.3, 125.6, 121.9, 119.2, 117.9, 116.9, 112.6,
10.5, 55.4, 52.0, 45.8, 31.9, 24.7, 17.6, 10.7. HRMS: m/z
[
M + Na] calcd for C H N O: 331.1786; found: 331.1786.
(
(
(
(
3) Kam, T.-S.; Sim, K.-M.; Lim, T.-M. Tetrahedron Lett. 2000,
20 24 2
(
17) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry: Reactions, Mechanisms and Structure; John
Wiley & Sons: New Jersey, 2007, 6th ed., 469–473.
18) For an ORTEP diagram of 12b, see the Supporting
Information. The crystal structure data have been deposited
with the Cambridge Crystallographic Data Centre (CCDC
4
1, 2733.
4) Irlinger, B.; Bartsch, A.; Kramer, H.-J.; Mayser, P.; Steglich,
W. Helv. Chim. Acta 2005, 88, 1472.
5) Wei, W.; Jiang, N.; Mei, Y. N.; Chu, Y. L.; Ge, H. M.; Song,
Y. C.; Ng, S. W.; Tan, R. X. Phytochemistry 2014, 100, 103.
6) Kraxner, J.; Hubner, H.; Gmeiner, P. Arch. Pharm. Pharm.
Med. Chem. 2000, 333, 287.
(
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2585–2590

2
590
J. E. Nidhiry, K. R. Prasad
LETTER
(22) For an ORTEP diagram of 18, see the Supporting
No. 1000488). The data can be accessed free of charge from
CCDC at: www.ccdc.cam.ac.uk/data_request/cif.
Information. The crystal structure data have been deposited
with the Cambridge Crystallographic Data Centre (CCDC
No. 980703).
(
(
19) The experimental procedures for the preparation of
compounds 11c–m are described in the Supporting
Information.
(23) For approaches towards the pentacyclic and tetracyclic cores
of tronocarpine, see: (a) Torres-Ochoa, R. O.; Reyes-
Gutiérrez, P. E.; Martínez, R. Eur. J. Org. Chem. 2014, 48.
(b) Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561.
(c) Also see ref. 13a.
20) The structure of E-isomer was elucidated by single crystal
X-ray diffraction analysis. For an ORTEP diagram, see the
Supporting Information. The crystal structure data have been
deposited with the Cambridge Crystallographic Data Centre
(
CCDC No. 980704).
(24) Grubbs, R. H. Angew. Chem. Int. Ed. 2006, 45, 3760;
Angew. Chem. 2006, 118, 3845.
(
21) The crystal structure data have been deposited with the
Cambridge Crystallographic Data Centre (CCDC No.
9
95842).
Synlett 2014, 25, 2585–2590
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.