Synthesis of cleavamine-type indole alkaloids and their 5-nor derivatives by a ring-closing metathesis-vinyl halide Heck cyclization strategy

Article abstract of DOI:10.1016/j.tet.2013.01.064

An indole-templated RCM has been used to assemble the central medium-sized rings of the indole upper-half of vinorelbine and the cleavamine-type alkaloids. From these key intermediates, the bridged tetracyclic framework of the alkaloids is completed with

Full text of DOI:10.1016/j.tet.2013.01.064

Tetrahedron 69 (2013) 2534e2541
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Synthesis of cleavamine-type indole alkaloids and their 5-nor
derivatives by a ring-closing metathesisevinyl halide Heck
cyclization strategy
,
b
,
,
,
,b
ꢀ a
M.-Lluïsa Bennasar a , Daniel Sole b, Ester Zulaica a b, Sandra Alonso a
*
a Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
b Institut de Biomedicina (IBUB), University of Barcelona, Barcelona 08028, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
An indole-templated RCM has been used to assemble the central medium-sized rings of the indole upper-
half of vinorelbine and the cleavamine-type alkaloids. From these key intermediates, the bridged tet-
racyclic framework of the alkaloids is completed with the insertion of a 2-ethylpropeno unit, by N-al-
kylation followed by a challenging endocyclic vinyl halide Heck cyclization. The usefulness of the
approach is illustrated with the synthesis of (ꢀ)-cleavamine and (ꢀ)-dihydrocleavamine.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 November 2012
Received in revised form 20 December 2012
Accepted 22 January 2013
Available online 31 January 2013
Keywords:
Alkaloids
Cleavamines
Ring-closing metathesis
Heck cyclization
1. Introduction
20
N
MeN
RCM
20
Heck
RCM
The remarkable structural diversity of indole alkaloids as well as
their significant biological activities have long caught the attention
of synthetic organic chemists, providing inspiration for the de-
velopment of novel synthetic strategies. Our longstanding interest
in this area led us to envisage a combination of two well-established
CeC bond-forming reactions, a ring-closing metathesis (RCM),1 and
a Heck cyclization,2 for the rapid assembly of the bridged tetracyclic
topography of some indole alkaloids. Based on this strategy, we have
recently developed a unique approach to the alkaloids ervitsine3
and apparicine.4 In particular, we have shown that after an indole-
templated RCM to build the central medium-sized ring of these al-
kaloids, a vinyl halide Heck coupling accomplishes the closure of the
piperidine ring with the concomitant placement of the exocyclic
20E-ethylidene substituent (Fig. 1). Other authors have also made
use of similar exocyclic vinyl halide Heck couplings for the assembly
of the bridged core of indole alkaloids including pentacyclic
Strychnos alkaloids,5 strychnine,6 and minfiensine.7
Heck
N
H
CH2
N
H
O
Apparicine
Ervitsine
Fig. 1. Previous applications of the RCMeHeck cyclization strategy.
(cleavamine, velbanamine, or (þ)-20R-dihydrocleavamine) are
a small subgroup of tetracyclic natural bases belonging to the Iboga
family8 that are structurally characterized by a central nine-
membered ring and a bridged 3-substituted piperidine moiety,
featuring a 1-azabicyclo[6.3.1]dodecane framework. The same tet-
racyclic skeleton is also found in the Aspidosperma alkaloid que-
brachamine. Cleavamines are of particular interest not only because
they have provided key synthetic intermediates for pentacyclic
Iboga derivatives9 but also because they constitute the indole up-
per-half of the well known antimitotic bisindole Catharanthus al-
kaloids vinblastine and vincristine.10 On the other hand, the 5-nor
tetracyclic architecture, featuring a 1-azabicyclo[5.3.1]undecane
bridged system, constitutes the indole upper-half of the semi-
synthetic derivative vinorelbine (50-noranhydrovinblastine), also
used in cancer chemotherapy.10,11
As an extension of our earlier work, we considered applying the
RCMeHeck double annulation strategy for the construction of other
bridged indolic structures, such as those included in cleavamines
and their 5-nor derivatives (Fig. 2). The cleavamine-type alkaloids
As depicted in Scheme 1, our synthetic plan for the assembly of
the bridged arrangements of the above alkaloids (I) commenced
* Corresponding author. Tel.: þ34 934024540; fax: þ34 934024539; e-mail ad-
dress: bennasar@ub.edu (M.-L. Bennasar).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.064

M.-L. Bennasar et al. / Tetrahedron 69 (2013) 2534e2541
2535
subsequent Heck coupling. This compound was easily prepared
applying a slight modification of our previously reported pro-
cedure.15 Thus, reductive amination of aldehyde 1 with allylamine
followed by protection of the resulting secondary amine with a Boc
group gave carbamate 2, which smoothly underwent RCM in the
presence of the second-generation Grubbs catalysts to give 3 in 58%
overall yield. At this point, access to the more advanced synthetic
intermediate 5 required the manipulation of the aliphatic nitrogen
to install the haloalkenyl chain. The N-Boc group was successfully
removed using a mild acid protocol (1.2 M HCl in MeOH at rt) and
the resulting secondary amine was directly alkylated with allylic
bromide 416 to give 5 in 60% overall yield. We also considered of
interest to prepare the respective indole-deprotected substrate 6,
which was accomplished by treatment of 5 with L-Selectride in
refluxing THF (62% yield). This reductive protocol was chosen to
minimize both the previsible isomerization of the double bond to
its indole-conjugated counterpart4 and the previsible elimination
of the haloalkenyl chain under the standard basic conditions.
H
OH
H
20
21
5
D
14
15
N
N
N
6
H
H
3
C
17
A
B
16
N
N
H
N
H
H
Cleavamine
(+)-20R-
Velbanamine
Dihydrocleavamine
N
N
n
H
N
OCOMe
CO2Me
N
N
H
CO2Me
MeO
H
N
OH
H
Me
Quebrachamine
Anhydrovinblastine n = 2
Vinorelbine n = 1
Boc
CHO
N
Fig. 2. Cleavamine, Catharanthus, and related alkaloids.
1. Allylamine
NaBH(OAc)3
N
N
2. (t-BuOCO)2O
SO2Ph
SO2Ph
65%
2
1
D
N
N
C
I
(ref. 15)
n
n
Heck
1. 1.2 M MeOH-HCl
2.
N
Boc
N
N
Mes
Ph
Mes
Cl
Cl
A
B
N
N
R
Ru
I
n = 1,2
R
4
(4)
Br
PCy3
I
5
Boc
N
Boc
N
CH2Cl2, reflux
89%
60%
SO2Ph
N
n
n
3
RCM
N
R
N
II
N
N
I
R
Pd(0)
Scheme 1. Synthetic strategy.
(see Table 1)
N
R
N
R
with the metathetic closure of appropriate 2,3-dialkenyl indoles to
provide the tricyclic ABC substructures II, containing a central
eight- or nine-membered ring.12 From these pivotal intermediates,
the carbon skeleton would be completed with the insertion of a 2-
ethylpropeno unit by N-alkylation followed by a challenging
endocyclic vinyl halide Heck cyclization upon the double bond left
by the RCM step. It should be noted that, apart from our own work
on the synthesis of apparicine,4 Heck cyclizations upon cyclo-
octenes or cyclononenes to produce strained bridged systems are
rare, most reported examples dealing with cyclizations from more
robust aryl halides.13
5 R = SO2Ph
6 R = H
L-selectride
THF
62%
Scheme 2. Access to the 1-azabicyclo[5.3.1]undecane bridged system.
A detailed investigation into the Heck reaction was then un-
dertaken using vinyl iodide 5 as the main substrate (Table 1). We
first examined the reaction under a cationic protocol (Pd(OAc)2,
PPh3, Ag2CO3, entry 1) similar to that successfully applied in our
synthesis of apparicine,4 but only the unchanged material was re-
covered using either refluxing toluene or acetonitrile as solvent.
Without the additive Ag2CO3, the inclusion of proton-spongeÒ as
base led to minor amounts of tetracycle 7, coming from the ex-
pected exo cyclization with the generation of a disubstituted
indole-conjugated double bond (entry 2). More satisfactorily, the
yield of 7 increased to 40% using Pd(PPh3)4 as the palladium cata-
lyst (entry 3). In both cases, minor amounts of another cyclized
product, not stable enough to be characterized, were detected in
the reaction mixtures.
This article describes the development of the above annulation
chemistry for the assembly of the 5-nor cleavamine skeleton and
the formulation of a novel synthetic approach to the alkaloids
cleavamine and dihydrocleavamine.14
2. Results and discussion
2.1. Heck cyclization upon azocino[4,3-b]indoles: access to 5-
nor cleavamines
The application of the latter conditions to the N-unsubstituted
indolic substrate 6 resulted in a cleaner cyclization, producing tet-
racycle 8 as the only product in 45% yield (entry 4). This compound
could be alternatively obtained by removal of the N-phenylsulfonyl
group of tetracycle 7 under standard basic conditions (67%,
We set out to study the construction of the 1-azabicyclo[5.3.1]
undecane bridged system (I, n¼1, Scheme 1), which defines the
indole upper-half of vinorelbine, targeting azocino[4,3-b]indole 3
(Scheme 2), with the 4,5-double bond functionality required for the

2536
M.-L. Bennasar et al. / Tetrahedron 69 (2013) 2534e2541
Table 1
Heck cyclization of vinyl iodides 5 and 6
N
N
N
N
I
OH
Pd(0)
+
+
N
N
N
N
SO2Ph
SO2Ph
R
R
10
9
7 R = SO2Ph
5 R = SO2Ph
6 R = H
8 R = H
Entry
Substrate
Conditions
Productsa (yield %)
1
2
3
4
5
5
5
5
6
5
Pd(OAc)2 (10%), PPh3 (30%), Ag2CO3 (2 equiv), toluene, or CH3CN, reflux, 24 h
5 (60)
Pd(OAc)2 (10%), PPh3 (40%), proton-spongeÒb (0.3 equiv), K2CO3 (1.5 equiv), toluene, reflux, 24 h
Pd(PPh3)4 (15%), proton-spongeÒ (0.1 equiv), K2CO3 (1.5 equiv), toluene, reflux 24 h
Pd(PPh3)4 (15%), proton-spongeÒ (0.1 equiv), K2CO3 (1.5 equiv), toluene, reflux 24 h
5 (45), 7 (15)c
7 (40)b
8 (45)
7 (25), 9 (24), 10 (20)
Pd2(dba)3 (7.5%), xantphos (15%), proton-spongeÒ (0.3 equiv), K2CO3 (1.5 equiv), toluene, reflux, 24 h
a
Isolated yields after column chromatography.
b
c
N,N,N0,N0-Tetramethyl-1,8-naphthalenediamine.
Minor amounts (10e15%) of an unidentified cyclization product were also formed.
Scheme 3). All attempts to selectively remove the disubstituted
5,6-position (e.g., 15 or 16, Scheme 4) and conclude with the for-
double bond of 8 by catalytic hydrogenation met with failure.
mation of the 3-ethylpiperidine ring.
OH
OH
1. LDA, THF,
then CuCN
N
N
TsCl, Et3N
6M NaOH
2. BrCH2CH=CH2
65%
DMAP
90%
N
N
THF-MeOH
67%
SO2Ph
SO2Ph
11
N
H
12
N
SO2Ph
7
8
Boc
OTs
N
Scheme 3. Indole deprotection of tetracycle 7.
H N
1.
2
K2CO3, CH3CN
On the other hand, the cyclization followed a different course in
the presence of Pd2(dba)3 and the bidentate ligand xantphos, in
which case vinyl iodide 5 led to a nearly equimolecular mixture of 7,
its double bond isomer 9, and carbinol 10 in a higher cyclization
yield (70%, entry 5). Carbinol 10 comes from the hydration of the
strained bridgehead double bond of 9, which is probably the result
N
2. (t-BuOCO)2O
N
SO2Ph
Et3N, MeOH
SO2Ph
14
13
75%
Boc
N
N
N
1. 1.2 M MeOH-HCl
Mes
Mes
Cl
Cl
of a direct
palladium intermediate rather than an isomerization process from
7. The different regioselectivity in the -elimination step in the
b-hydride elimination from the initially formed s-alkyl
Ph
2.
Ru
Br
5
b
PCy3
(4)
I
6
presence of xantphos proved to be crucial for our successful Heck
cyclization in the higher homologous series (see below).
While the 1H NMR spectra of tetracycles 8, 9, and 10 exhibited
clear resonances at room temperature, which allowed their un-
eventful structural determination, tetracycle 7 showed broad sig-
nals, implying the existence of two conformational states in
solution with a high barrier to interconversion. Upon inspection of
the 1H NMR at a lower temperature (ꢁ30 ꢂC) two sets of clear
signals in a 2:1 ratio were observed. The assignment was completed
by analysis of 13C NMR data (ꢁ10 ꢂC) with the aid of bidimensional
techniques (HSQC).
N
CH2Cl2, reflux
75%
R
15 R = SO2Ph
16 R = H
Mg, MeOH
84%
N
N
I
Pd(0)
N
R
N
R
17 R = SO2Ph 79%
18 R = H 44%
2.2. Synthesis of cleavamines
Scheme 4. Access to the 1-azabicyclo[6.3.1]dodecane bridged system.
Attention was then focused on the application of the RCMeHeck
cyclization strategy to assemble the 1-azabicyclo[6.3.1]dodecane
bridged framework (I, n¼2, Scheme 1), which defines the tetracy-
clic architecture of the cleavamine alkaloids.14 As stated before, the
sequential ring formation would start with the construction of
a suitable azonino[5,4-b]indole incorporating a double bond at the
The synthetic route to the key intermediate 15 began with the
preparation of the diene precursor 14 by successive introduction of
the required alkenyl appendages from the known tryptophol 11,17
which was equipped with a robust phenylsulfonyl at the indole

M.-L. Bennasar et al. / Tetrahedron 69 (2013) 2534e2541
2537
nitrogen as in the above series. Exposure of 11 to excess LDA and
CuCN followed by reaction of the intermediate organocopper with
allyl bromide led to 2-allylindole 12 (65%). This was uneventfully
converted into diene 14 by treatment of the corresponding tosylate
13 with allylamine and subsequent protection of the resulting
secondary amine (75% for the two steps).
The next issue to be tackled was the closure of the nine-
membered by RCM.13b,18 We expected that, as in our previous
synthesis of azocinoindoles,4,15 both the fused indole ring and the
nitrogen carbamate would operate synergistically, thus favoring
the desired cyclization. Satisfactorily, RCM of diene 14 proceeded
smoothly in the presence of the second-generation Grubbs catalyst
in refluxing CH2Cl2. The reaction was completed in a short reaction
time (2 h 30 min) and azoninoindole 15, with the Z configuration of
the double bond, was isolated in 75% yield.
N
N
I
Pd2(dba)3, xantphos
K2CO3, 1:1 toluene-TEA
80ºC, 1.5 h
N
R
N
R
17 R = SO2Ph
18 R = H
19 R = SO2Ph 85%
20 R = H 74%
Mg, MeOH
88%
N
N
Our following task was to install the haloalkenyl chain required
for the subsequent Heck reaction. Thus, removal of the Boc group of
15 in mild acid conditions and direct alkylation of the resulting
secondary amine with bromide 4 as in the above series led to vinyl
iodide 17 in 79% overall yield. In turn, the respective indole-
deprotected substrate 18 was prepared from 15 by reductive re-
moval of the phenylsulphonyl group using Mg in MeOH (84%),
followed by derivatization of the aliphatic nitrogen of the resulting
compound 16 according to the usual protocol (44%).
N
SO2Ph
N
SO2Ph
21
22
Scheme 5. Heck cyclization of vinyl halides 17 and 18.
H
20
14
N
The availability of substrate 17 allowed us to examine the
intramolecular coupling of the vinyl iodide and the disubstituted
double bond included in the azonine ring to complete the bridged
tetracyclic framework of cleavamines. We expected tetracycle 21 to
be preferentially formed as a result of an exo cyclization with
generation of an indole-conjugated double bond. However, under
a variety of conditions, including palladium precatalysts [Pd(PPh3)4,
Pd2dba3], ligands (BINAP, dppe), and additives (proton-sponge,
Et3N, diisopropylethylamine) in refluxing toluene, we only ob-
tained mixtures of the starting material and variable amounts of
tetracycle 22, which presumably arose from 21 by oxidation. Al-
though we were able to isolate 21 using shorter reaction times or
lower temperatures, it proved to be highly unstable, slowly being
converted into 22 under the extractive workup or column chro-
matography.19 We then examined the Heck cyclization in the
presence of the phosphine xantphos, expecting a different regio-
selectivity in the elimination step as in our previous synthesis of 5-
nor cleavamines, which would avoid the undesirable formation of
22. To our delight, the outcome of the cyclization changed com-
pletely on exposure of 17 to Pd2dba3/xantphos and K2CO3 in tol-
ueneeEt3N at 80 ꢂC for a short reaction time (1.5 h). Tetracycle 19,
embodying a trisubstituted bridgehead double bond, was isolated
in a yield as high as 85%. In contrast to its regioisomer 21, tetracycle
19 showed no tendency to undergo oxidation. The application of
this protocol to the indole-deprotected substrate 18 similarly led to
tetracycle 20 (74%), which was alternatively obtained by depro-
tection of 19 (88%) under reductive conditions (Scheme 5).
With the 1-azabicyclo[6.3.1]dodecane framework in hand, the
synthesis of (ꢀ)-cleavamine only required the selective reduction
of the bridgehead double bond. When tetracycle 20 was subjected
to catalytic hydrogenation in AcOEt, (ꢀ)-cleavamine (23) was iso-
lated as the major product (40% yield) after a short reaction time
(1 h), although minor amounts of 14,20-cis-dihydrocleavamine (24)
were also formed (Scheme 6). As expected, longer reaction times
(5 h) gave 24 as the only product (43%). Synthetic cleavamines
displayed 1H and 13C NMR spectral data identical to that reported
for the natural products.20,21
N
H
H2, PtO2
AcOEt, rt
20
+
N
H
N
H
24 (20%)
24 (43%)
23 (40%)
23 ( )
reaction time: 1h
reaction time: 5h
Scheme 6. Completion of the synthesis of cleavamines.
derivatives combining an RCM with an endocyclic vinyl halide Heck
cyclization. The synthesis of (ꢀ)-cleavamine and (ꢀ)-dihy-
drocleavamine significantly expands the scope and potential of this
double annulation strategy for the synthesis of bridged indole
alkaloids.
4. Experimental section
4.1. General
All nonaqueous reactions were carried out under an argon at-
mosphere. All solvents were dried by standard methods. Reaction
courses and product mixtures were routinely monitored by TLC on
SiO2 (silica gel 60 F254) and the spots were located with aqueous
potassium permanganate solution. Drying of organic extracts was
carried out over anhydrous Na2SO4. The solvents were evaporated
under reduced pressure with a rotary evaporator. Unless otherwise
indicated, column chromatography was carried out using the flash
chromatography technique on SiO2 (silica gel 60, SDS,
0.04e0.06 mm). NMR spectra were recorded in CDCl3 using Me4Si
as an internal reference. HRMS were obtained using an LC/MSD TOF
mass spectrometer.
4.2. Synthesis of 5-nor cleavamines
4.2.1. 2-(tert-Butoxycarbonyl)-7-(phenylsulfonyl)-1,2,3,6-tetrahydr-
oazocino[4,3-b]indole (3).15 The second-generation Grubbs catalyst
(23 mg, 0.026 mmol) was added under Ar to a solution of diene 215
(180 mg, 0.38 mmol) in CH2Cl2 (10 mL) and the resulting mixture
was heated at reflux for 2 h. The reaction mixture was concentrated
3. Conclusions
We have developed a concise entry to the strained tetracyclic
arrangement of the cleavamine alkaloids and their 5-nor

2538
M.-L. Bennasar et al. / Tetrahedron 69 (2013) 2534e2541
and the residue was chromatographed (1:1 hexanes/AcOEt) to give
the title compound 3 as a white foam: 0.34 g (89%).
1H), 0.79 (m, 1H), 2.59 (masked, 1H), 2.78 (d, J¼18 Hz, 1H),
3.00e3.10 (m, 3H), 3.20 (d, J¼15 Hz, 1H), 3.91 (s, 1H), 4.61 (d,
J¼15 Hz, 1H), 6.30 (dd, J¼12 and 9 Hz, 1H), 7.02 (d, J¼12 Hz, 1H),
7.20e7.75 (m, 7H), 7.85 (d, J¼8 Hz, 1H), 8.21 (d, J¼10 Hz, 1H); 13C
4.2.2. 2-(2-Ethyl-3-iodo-2-propenyl)-7-(phenylsulfonyl)-1,2,3,6-
tetrahydroazocino[4,3-b]indole (5). A solution of carbamate
3
NMR (100.6 MHz, ꢁ10 ꢂC, major conformer)
d 11.8 (CH3), 27.9 (CH2),
(450 mg, 1.03 mmol) in 1.2 M HCl in MeOH (4.2 mL) was stirred at rt
for 18 h. The reaction mixture was basified with 20% NH4OH and
concentrated. The residue was partitioned between CH2Cl2 and H2O
and extracted with CH2Cl2. The organic extracts were dried and
concentrated to give the crude secondary amine (278 mg). Diiso-
propylethylamine (0.2 mL, 1.16 mmol) and (Z)-2-(bromomethyl)-1-
iodo-1-butene16 (4, 235 mg, 0.82 mmol) were added to a solution of
the above amine in 1:1 CH2Cl2/acetonitrile (16 mL) and the
resulting mixture was stirred at rt overnight. The solvent was re-
moved and the residue was dissolved in CH2Cl2 and washed with
10% aqueous NaHCO3. The organic solution was dried and con-
centrated to give the crude product. After column chromatography
(8:2 hexanes/AcOEt), the title compound 5 was obtained as an oil:
34.3 (CH), 43.8 (CH2), 44.9 (CH2), 55.5 (CH2), 115.2 (CH), 115.8 (CH),
116.9 (C), 118.6 (C), 118.8 (CH), 120.9 (CH), 124.3 (CH), 125.2 (CH),
126.3 (2 CH), 128.8 (2 CH), 130.0 (C), 133.8 (CH), 135.3 (C), 135.8
(CH), 136.5 (C), 136.9 (C); minor conformer: 11.0 (CH3), 27.4 (CH2),
32.9 (CH), 48.9 (CH2), 49.1 (CH2), 53.5 (CH2), 114.1 (CH), 117.4 (CH),
119.9 (CH), 123.4 (CH), 124.5 (CH), 126.0 (CH), 127.1 (2 CH), 129.2 (2
CH), 130.7 (C), 131.9 (CH), 134.0 (C), 137.4 (CH), 138.6 (C), three
quaternary C were not observed; ESI-HRMS [MþH]þ calcd for
C24H25N2O2S 405.1631, found 405.1628.
Table 1, entry 5. Pd2(dba)3 (5.5 mg, 0.006 mmol), xantphos (7 mg,
0.012 mmol), proton-spongeÒ (5 mg, 0.023 mmol), and K2CO3
(16.5 mg, 0.12 mmol) were added under Ar to a solution of vinyl
iodide 5 (42 mg, 0.079 mmol) in toluene (8 mL), and the resulting
solution was heated at reflux for 24 h. Workup as above and column
chromatography (from CH2Cl2 to 94:6 CH2Cl2/MeOH) gave 7 (8 mg,
25%), 9 (7.7 mg, 24%), and 10 (6.7 mg, 20%). 4-Ethyl-9-(phenyl-
327 mg (60%); 1H NMR (400 MHz)
d
1.06 (t, J¼7.6 Hz, 3H), 2.29 (q,
J¼7.6 Hz, 2H), 3.07 (d, J¼6.8 Hz, 2H); 3.26 (s, 2H), 3.90 (s, 2H), 4.05
(d, J¼6 Hz, 2H), 5.60 (m, 1H), 5.99 (m, 1H), 6.04 (br s, 1H), 7.28 (m,
2H), 7.40 (m, 3H), 7.54 (dd, J¼7.6 and 7.2 Hz, 1H), 7.76 (dd, J¼8.8 and
1.2 Hz, 2H), 8.23 (dd, J¼8.4 and 0.8 Hz, 1H); 13C NMR (74.5 MHz)
sulfonyl)-1,2,3,8-tetrahydro-2,6-methanoazecino[4,3-b]indole
(9):
0.99 (t, J¼7.5 Hz, 3H),1.91 (q, J¼7.5 Hz, 2H),
oil; 1H NMR (500 MHz)
d
d
12.6 (CH3), 26.6 (CH2), 29.5 (CH2), 47.0 (CH2), 49.1 (CH2), 60.6
2.90 (d, J¼18 Hz, 1H), 3.03 (d, J¼12.5 Hz, 1H), 3.32 (d, J¼12.5 Hz, 1H),
3.49 (d, J¼12 Hz, 1H), 3.70 (dd, J¼19 and 5.5 Hz, 1H), 3.70 (m, 2H),
3.83 (dd, J¼19 and 8 Hz, 1H), 5.73 (dd, J¼8 and 5 Hz, 1H), 6.05 (s,
1H), 7.19e7.24 (m, 2H), 7.33 (t, J¼7.5 Hz, 2H), 7.45 (tt, J¼7.5 and
1.5 Hz, 1H), 7.50 (dd, J¼7.5 and 1.5 Hz, 1H), 7.61 (m, 2H), 8.16 (d,
(CH2), 76.7 (CH), 115.0 (CH), 117.0 (C), 118.0 (CH), 123.7 (CH), 124.3
(CH), 126.2 (2 CH), 126.6 (CH), 129.0 (C), 129.2 (2 CH), 129.5 (CH),
133.6 (CH), 136.4 (C), 137.1 (C), 139.0 (C), 150.6 (C); ESI-HRMS
[MþH]þ calcd for C24H26IN2O2S 533.0754, found 533.0757.
J¼7.5 Hz, 1H); 13C NMR (125.7 MHz, HSQC)
d 12.1 (CH3), 26.7 (CH2),
4.2.3. 5-(2-Ethyl-3-iodo-2-propenyl)-1,2,3,6-tetrahydroazocino[4,3-
27.6 (CH2), 44.1 (CH2), 49.2 (CH2), 56.8 (CH2), 114.7 (CH), 117.5 (CH),
118.0 (CH),122.3 (CH),123.6 (CH),124.6 (CH),126.1 (2 CH),128.9 (C),
129.3 (2 CH), 131.0 (C), 133.5 (C), 133.7 (CH), 136.4 (C), 137.6 (C),
139.2 (C), one quaternary C was not observed; ESI-HRMS [MþH]þ
calcd for C24H25N2O2S 405.1631, found 405.1630. 4-Ethyl-6-
hydroxy-9-(phenylsulfonyl)-1,2,3,6,7,8-hexahydro-2,6-
b]indole (6). L-Selectride (0.66 mL of
1 M solution in THF,
0.66 mmol) was added under Ar to a solution of azocinoindole 5
(35 mg, 0.066 mmol) in THF (5 mL). After being heated at reflux for
1 h, the reaction mixture was quenched with MeOH, diluted with
H2O, and extracted with AcOEt. The organic extracts were washed
with brine, dried, and concentrated and the resulting residue was
purified by column chromatography (from CH2Cl2 to 97:3 CH2Cl2/
methanoazecino[4,3-b]indole (10): oil; 1H NMR (300 MHz)
d 0.80 (t,
J¼7.5 Hz, 3H), 1.56 (dq, J¼8.4 and 7.5 Hz, 1H), 1.71 (dq, J¼8.4 and
7.5 Hz, 1H), 1.89 (ddd, J¼13.8, 8.1, and 3 Hz, 1H), 2.08 (ddd, J¼13.8,
9.9, and 3 Hz, 1H), 2.89 (d, J¼14.7 Hz, 1H), 2.98 (d, J¼17.4 Hz, 1H),
3.10 (ddd, J¼12, 8.1, and 3 Hz, 1H), 3.15 (d, J¼14.7 Hz, 1H), 3.38 (ddd,
J¼12, 9.9, and 3 Hz, 1H), 3.52 (d, J¼17.4 Hz, 1H), 3.91 (d, J¼13.5 Hz,
1H), 4.00 (d, J¼13.5 Hz, 1H), 5.18 (s, 1H), 7.24e7.33 (m, 2H), 7.42 (dd,
J¼7.6 and 1.2 Hz, 2H), 7.53 (tt, J¼7.6 and 1.2 Hz, 1H), 7.57 (d, J¼8 Hz,
1H), 7.76 (m, 2H), 8.21 (dd, J¼7.2 and 1.2 Hz, 1H); 13C NMR
MeOH) to give 6 as an oil: 16 mg (62%); 1H NMR (400 MHz)
d 1.10 (t,
J¼7.6 Hz, 3H), 2.41 (qd, J¼7.6 and 1.2 Hz, 2H), 3.14 (d, J¼7.6 Hz, 2H),
3.35 (s, 2H), 3.70 (d, J¼4.8 Hz, 2H), 3.97 (s, 2H), 5.79 (q, J¼7.6 Hz,
1H), 6.00e6.12 (m, 2H), 7.07e7.15 (m, 2H), 7.27 (dd, J¼6 and 1.6 Hz,
1H), 7.50 (dd, J¼6.8 and 1.6 Hz, 1H), 7.87 (br, 1H); 13C NMR
(100.5 MHz)
d 12.6 (CH3), 27.7 (CH2), 29.5 (CH2), 45.9 (CH2), 48.0
(CH2), 60.7 (CH2), 77.2 (CH), 110.0 (CH), 117.7 (CH), 119.6 (CH), 121.3
(CH), 126.9 (br CH), 128.8 (br CH), 129.5 (C), 134.8 (C), 135.3 (C),
150.5 (C), one quaternary C was not observed; ESI-HRMS [MþH]þ
calcd for C18H22IN2 393.0822, found 393.0823.
(125.7 MHz, HSQC)
d 11.2 (CH3), 21.8 (CH2), 27.6 (CH2), 39.4 (CH2),
46.5 (CH2), 52.4 (br CH2), 56.3 (CH2), 67.7 (C), 114.7 (CH), 118.6 (CH),
123.9 (CH), 124.8 (CH), 125.2 (CH), 126.2 (2 CH), 128.8 (C), 129.4 (2
CH), 133.9 (CH), 136.3 (C), 139.1 (C), three quaternary C were not
observed; ESI-HRMS [MþH]þ calcd for C24H27N2O3S 423.1737,
found 423.1735.
4.2.4. Heck cyclization of vinyl iodide 5. Table 1, entry 3. Pd(PPh3)4
(15 mg, 0.013 mmol), proton-spongeÒ (5.5 mg, 0.025 mmol), and
K2CO3 (18 mg, 0.13 mmol) were added under Ar to a solution of
vinyl iodide 5 (45 mg, 0.085 mmol) in toluene (8.5 mL), and the
resulting solution was heated at reflux for 24 h. The solvent was
removed and the residue was partitioned between CH2Cl2 and
a saturated aqueous NaHCO3 solution. The organic layer was dried
and concentrated and the resulting residue was purified by col-
umn chromatography (from CH2Cl2 to 98:2 CH2Cl2/MeOH). A
second column chromatography (from Et2O to 99:1 Et2O/diethyl-
amine) led to 4-ethyl-9-(phenylsulfonyl)-1,2,3,6-tetrahydro-2,6-
methanoazecino[4,3-b]indole (7) as an oil: 14 mg (40%); 1H NMR
4.2.5. 4-Ethyl-1,2,3,6-tetrahydro-2,6-methanoazecino[4,3-b]indole
(8). From vinyl iodide 6. Vinyl iodide 6 (20 mg, 0.05 mmol) in tol-
uene (4.5 mL) was allowed to react with Pd(PPh3)4 (11.5 mg,
0.01 mmol), proton-spongeÒ (2.1 mg, 0.01 mmol), and K2CO3
(10 mg, 0.075 mmol) as described in Table 1, entry 3. After being
heated at reflux for 16 h, the usual workup and column chroma-
tography (from Et2O to 98:2 Et2O/diethylamine) gave tetracycle 8 as
an oil: 6 mg (45%); 1H NMR (400 MHz)
d
0.89 (t, J¼7.6 Hz, 3H), 1.87
(m, 2H), 2.85 (dd, J¼12.4 and 5.6 Hz, 1H), 2.87 (br s, 1H), 3.15 (d,
J¼17.2 Hz, 1H), 3.35 (d, J¼12.4 Hz, 1H), 3.69 (d, J¼17.2 Hz, 1H), 3.90
(d, J¼12.8 Hz, 1H), 4.11 (d, J¼12.8 Hz,1H), 5.51 (s, 1H), 5.95 (dd, J¼12
and 5.6 Hz, 1H), 6.33 (d, J¼12 Hz, 1H), 7.09e7.17 (m, 2H), 7.30 (d,
J¼7.6 Hz, 1H), 7.67 (d, J¼8.4 Hz, 1H), 8.07 (br, 1H); 13C NMR
(500 MHz, ꢁ30 ꢂC, major conformer)
d
0.99 (t, J¼7.5 Hz, 3H), 1.93
(m, 2H), 2.40 (dd, J¼14 and 4.5 Hz, 1H), 2.59 (d, J¼14 Hz, 1H), 2.70
(br s, 1H), 3.05 (d, J¼17.5 Hz, 1H), 3.66 (d, J¼17.5 Hz, 1H), 3.72 (d,
J¼11 Hz, 1H), 3.77 (d, J¼11 Hz, 1H), 5.60 (s, 1H), 5.90 (dd, J¼12.5
and 4.5 Hz, 1H), 6.70 (d, J¼12.5 Hz, 1H), 7.20e7.75 (m, 8H), 8.19 (d,
J¼8.5 Hz, 1H); minor conformer: ꢁ0.55 (t, J¼7.5 Hz, 3H), 0.62 (m,
(100.5 MHz)
d 11.8 (CH3), 28.1 (CH2), 34.6 (CH), 43.3 (CH2), 46.2
(CH2), 54.0 (CH2), 110.6 (CH), 116.7 (CH), 117.7 (C), 118.6 (CH), 120.0

M.-L. Bennasar et al. / Tetrahedron 69 (2013) 2534e2541
2539
(CH), 120.7 (CH), 122.2 (CH), 128.2 (C), 135.3 (C), 135.8 (CH), 135.9
(C), 136.5 (C); ESI-HRMS [MþH]þ calcd for C18H21N2 265.1699,
found 265.1698.
2.86 mmol), and a catalytic amount of LiI in CH3CN (35 mL) was
stirred at 85 ꢂC in a sealed tube for 48 h. The reaction mixture was
concentrated and the resulting residue was diluted with CH2Cl2
and washed with a saturated aqueous Na2CO3 solution. The organic
layer was dried and concentrated to give the crude secondary
amine (540 mg). A solution of the above amine, triethylamine
(0.7 mL, 5.0 mmol), and (t-BuOCO)2O (530 mg, 2.43 mmol) in
MeOH (18 mL) was heated at reflux for 5 h. The solvent was re-
moved and the residue was diluted with CH2Cl2 and washed with
2 N HCl and brine. The organic extracts were dried and concen-
trated to give the crude product. After column chromatography
(from hexanes to 4:1 hexanes/AcOEt), diene 14 was obtained as an
From tetracycle 7. 6 M aqueous NaOH solution (2 mL) was
added to a solution of tetracycle 7 (18 mg, 0.044 mmol) in a 1:3
mixture of THF/MeOH (6 mL). After being heated at 85 ꢂC for 3 h,
the reaction mixture was poured into a saturated aqueous NH4Cl
solution. The organic solvent was removed and the resulting res-
idue was partitioned between CH2Cl2 and brine. The organic layer
was dried and concentrated and the residue was purified by col-
umn chromatography (from Et2O to 98:2 Et2O/diethylamine) to
give 8: 8 mg (67%).
oil: 516 mg (75%); 1H NMR (400 MHz, mixture of rotamers)
d 1.48
4.3. Synthesis of cleavamines
(s, 9H), 2.86 (br, 2H), 3.28 (br, 2H), 3.46 (br, 1H), 3.69 (br, 1H), 3.80
(d, J¼6 Hz, 2H), 4.90e5.15 (m, 4H), 5.65 (br, 1H), 6.00 (m, 1H),
7.22e7.32 (m, 2H), 7.35e7.40 (m, 2H), 7.45e7.52 (m, 2H), 7.72 (d,
J¼8 Hz, 2H), 8.19 (d, J¼7.6 Hz, 1H); 13C NMR (100.5 MHz, mixture of
4.3.1. 2-Allyl-3-(2-hydroxyethyl)-1-(phenylsulfonyl)indole
(12). A
solution of diisopropylamine (0.7 mL, 4.99 mmol) in THF (21 mL)
was cooled to ꢁ78 ꢂC and n-BuLi (2.5 M in hexanes, 1.8 mL,
4.5 mmol) was slowly added. The resulting solution was stirred at
ꢁ78 ꢂC for 30 min and a solution of tryptophol 1117 (0.52 g,
1.73 mmol) in THF (10 mL) was added dropwise. The reaction
mixture was allowed to warm to ꢁ50 ꢂC (1 h) and CuCN (196 mg,
2.19 mmol) was added. The reaction mixture was allowed to warm
to rt and then was cooled again to ꢁ78 ꢂC. Allyl bromide (0.17 mL,
1.96 mmol) was added, the reaction mixture was allowed to warm
to rt, and the stirring was continued at rt for 12 h. The reaction
mixture was diluted with 20% NH4OH and extracted with CH2Cl2.
The organic extracts were dried and concentrated and the resulting
residue was chromatographed (from hexanes to 7:3 hexanes/
AcOEt) to give the title compound 12 as an oil: 383 mg (65%); 1H
rotamers)
d 23.0 (CH2), 23.6 (CH2), 28.4 (CH3), 30.0 (CH2), 46.1
(CH2), 46.7 (CH2), 49.8 (CH2), 50.8 (CH2), 79.5 (C), 79.8 (C), 115.1
(CH), 116.1 (CH2), 116.7 (CH2), 118.4 (CH), 118.7 (CH), 119.1 (C), 119.5
(C), 123.5 (CH), 124.4 (CH), 126.2 (2 CH), 129.0 (2 CH), 130.3 (C),
133.5 (CH), 134.1 (CH), 135.1 (C), 135.3 (CH), 136.5 (C), 138.9 (C),
155.1 (C); ESI-HRMS [MþH]þ calcd for C27H33N2O4S 481.2181,
found 481.2182.
4.3.4. 3-(tert-Butoxycarbonyl)-8-(phenylsulfonyl)-2,3,4,7-
tetrahydro-1(H)-azonino[5,4-b]indole (15). The second-generation
Grubbs catalyst (30 mg, 0.035 mmol) was added under Ar to a so-
lution of diene 14 (240 mg, 0.5 mmol) in CH2Cl2 (30 mL) and the
resulting mixture was heated at reflux for 2 h 30 min. The reaction
mixture was concentrated and the residue was purified by column
chromatography (from hexanes to 4:1 hexanes/AcOEt) to give tri-
cyclic carbamate 15 as a white foam: 170 mg (75%); 1H NMR
NMR (400 MHz)
d
2.92 (t, J¼6.8 Hz, 2H), 3.78 (t, J¼6.8 Hz, 2H), 3.85
(dt, J¼6 and 1.6 Hz, 2H), 4.99e5.07 (m, 2H), 6.04 (ddt, J¼17.2, 10.4,
and 6 Hz, 1H), 7.26 (td, J¼7.6 and 0.8 Hz, 1H), 7.32 (ddd, J¼8, 7.6, and
1.6 Hz, 1H), 7.39 (td, J¼7.2 and 1.6 Hz, 2H), 7.46e7.53 (m, 2H), 7.74
(dd, J¼7.2 and 1.6 Hz, 2H), 8.21 (d, J¼7.6 Hz, 1H); 13C NMR
(400 MHz, mixture of rotamers)
d 1.28 and 1.44 (2s, 9H), 2.97 (m,
2H), 3.37e3.47 (m, 3.1H), 3.55 (m, 0.9H), 3.77 (d, J¼6.8 Hz, 2H), 5.56
(dt, J¼11.6 and 4.8 Hz, 0.55H), 5.73 (dt, J¼11.2 and 4.8 Hz, 0.45H),
6.09 (m, 1H), 7.21e7.30 (m, 2H), 7.33e7.42 (m, 3H), 7.47 (t, J¼7.6 Hz,
1H), 7.71 (m, 2H), 8.10 (m, 1H); 13C NMR (100.5 MHz, mixture of
(100.5 MHz)
d 27.7 (CH2), 30.1 (CH2), 61.8 (CH2), 115.1 (CH), 116.0
(CH2), 118.4 (C), 118.6 (CH), 123.5 (CH), 124.4 (CH), 126.2 (2 CH),
129.0 (2 CH), 130.3 (C), 133.5 (CH), 135.5 (CH), 135.6 (C), 136.5 (C),
138.7 (C); ESI-HRMS [MþH]þ calcd for C19H20NO3S 342.1158, found
342.1159.
rotamers)
d 23.8 (CH2), 23.9 (CH2), 24.1 (CH2), 24.2 (CH2), 28.2
(CH3), 28.4 (CH3), 43.3 (CH2), 47.4 (CH2), 48.2 (CH2), 48.3 (CH2), 79.5
(C), 79.7 (C), 114.9 (CH), 115.0 (CH), 117.6 (C), 118.1 (CH), 118.2 (CH),
118.9 (C), 123.3 (CH), 123.5 (CH), 124.3 (CH), 124.5 (CH), 126.2 (2
CH),126.3 (2 CH),127.7 (CH),128.6 (CH), 129.0 (2 CH),129.05 (2 CH),
129.1 (CH), 129.7 (CH), 133.4 (CH), 133.5 (CH), 134.7 (C), 136.1 (C),
136.4 (C), 136.6 (C), 138.9 (C), 139.1 (C), 154.9 (C), 155.7 (C); ESI-
HRMS [MþNa]þ calcd for C25H28N2NaO4S 475.1662, found
475.1664.
4.3.2. Tosylate 13. p-Toluenesulfonyl chloride (0.63 g, 3.3 mmol),
triethylamine (1.1 mL, 7.89 mmol), and DMAP (catalytic amount)
were added to a solution of tryptophol 12 (1.02 g, 2.99 mmol) in
CH2Cl2 (20 mL), and the resulting mixture was stirred at rt over-
night. The reaction mixture was diluted with CH2Cl2 and succes-
sively washed with 1 N HCl and a saturated aqueous NaHCO3
solution. The organic layer was dried and concentrated and the
resulting residue was chromatographed (from hexanes to 4:1
hexanes/AcOEt) to give tosylate 13 as an oil: 1.33 g (90%); 1H NMR
4.3.5. 3-(tert-Butoxycarbonyl)-2,3,4,7-tetrahydro-1(H)-azonino[5,4-
b]indole (16). Mg (230 mg, 9.46 mmol) was added to a solution of
carbamate 15 (425 mg, 0.94 mmol) in MeOH (37 mL) cooled to 0 ꢂC.
After being stirred at rt for 4 h, the reaction mixture was poured
into H2O (80 mL). Warm CH2Cl2 (200 mL) was added and the
mixture was gently stirred for 30 min. The organic layer was sep-
arated and the aqueous layer was extracted with CH2Cl2. The
combined organic extracts were dried and concentrated to give the
title compound 16: 248 mg (84%); 1H NMR (400 MHz, mixture of
(400 MHz)
d
2.38 (s, 3H), 2.98 (t, J¼6.8 Hz, 2H), 3.75 (d, J¼6 Hz, 2H),
4.12 (t, J¼6.8 Hz, 2H), 4.91 (dd, J¼17.2 and 1.2 Hz, 1H), 4.96 (dd, J¼10
and 1.2 Hz, 1H), 5.89 (ddt, J¼17.2, 10, and 6 Hz, 1H), 7.13 (d, J¼7.6 Hz,
2H), 7.18 (t, J¼7.6 Hz, 1H), 7.25e7.30 (m, 2H), 7.35e7.40 (m, 2H),
7.46e7.51 (m, 3H), 7.72 (d, J¼7.6 Hz, 2H), 8.14 (d, J¼7.6 Hz, 1H); 13C
NMR (100.5 MHz)
d 21.4 (CH3), 24.1 (CH2), 29.9 (CH2), 68.5 (CH2),
114.8 (CH), 116.0 (C), 116.1 (CH2), 118.1 (CH), 123.4 (CH), 124.3 (CH),
126.2 (2 CH), 127.4 (2 CH), 129.1 (2 CH), 129.5 (2 CH), 132.2 (C), 133.6
(CH), 134.9 (CH), 135.9 (C), 136.2 (C), 138.7 (C), 144.6 (C), one qua-
ternary C was not observed; ESI-HRMS [MþNH4]þ calcd for
C26H29N2O5S2 513.1512, found 513.1507; ESI-HRMS [MþNa]þ calcd
for C26H25NNaO5S2 518.1066, found 518.1060.
rotamers) d 1.29 and 1.45 (2 s, 9H), 3.05 (m, 2H), 3.42 (m, 3H), 3.49
(m, 2H), 3.69 (d, J¼4.4 Hz, 1H), 5.58 (m, 0.5H), 5.72 (m, 0.5H), 5.84
(m, 1H), 7.05e7.14 (m, 2H), 7.25 (d, J¼7.6 Hz, 1H), 7.48 (m, 1H), 7.81
and 7.85 (2 br s, 1H); 13C NMR (100.5 MHz, mixture of rotamers)
d
23.3 (CH2), 23.6 (CH2), 24.5 (CH2), 25.1 (CH2), 28.2 (CH3), 28.4
(CH3), 47.2 (CH2), 47.5 (CH2), 49.7 (CH2), 79.3 (C), 79.5 (C), 109.3 (C),
110.0 (C), 110.2 (CH), 110.3 (CH), 117.5 (CH), 117.8 (CH), 118.9 (CH),
119.0 (CH), 121.1 (CH), 121.2 (CH), 126.0 (CH), 126.1 (CH), 127.5 (C),
128.2 (C), 129.9 (CH), 130.7 (CH), 132.6 (C), 132.9 (C), 135.3 (C), 135.6
4.3.3. 2-Allyl-3-[2-(N-allyl-N-tert-butoxycarbonylamino)ethyl]-1-
(phenylsulfonyl)indole (14). A mixture of tosylate 13 (0.71 g,
1.43 mmol), allylamine (0.8 mL, 10.7 mmol), K2CO3 (395 mg,

2540
M.-L. Bennasar et al. / Tetrahedron 69 (2013) 2534e2541
(C), 155.3 (C), 155.9 (C); ESI-HRMS [MþH]þ calcd for C19H25N2O2
and 4 Hz, 1H, 16-H), 5.41 (dd, J¼11 and 4 Hz, 1H, 17-H), 6.32 (s, 1H,
15-H), 7.20 (ddd, J¼7.5, 6.5, and 1 Hz, 1H, 10-H), 7.24 (dm, J¼7.5 Hz,
1H, 9-H), 7.26 (ddd, J¼8.5, 6.5, and 1 Hz, 1H, 11-H), 7.43 (m, 2H),
7.54 (tt, J¼7.5 and 1.5 Hz, 1H), 7.75 (m, 2H), 8.21 (dt, J¼8.5 and 1 Hz,
1H, 12-H); 13C NMR (125.7 MHz, assignment aided by HSQC and
313.1911, found 313.1910.
4.3.6. 3-[(Z)-2-Ethyl-3-iodo-2-propenyl]-8-(phenylsulfonyl)-2,3,4,7-
tetrahydro-1(H)-azonino[5,4-b]indole (17). A solution of carbamate
15 (243 mg, 0.54 mmol) in 1.2 M HCl in MeOH (25 mL) was stirred at
rt for 5 h. The reaction mixture was basified with 20% NH4OH and
concentrated. The residue was partitioned between CH2Cl2 and H2O
and extracted with CH2Cl2. The organic extracts were dried and
concentrated to give the crude secondary amine (182 mg). This
material was allowed to react with diisopropylethylamine (0.14 mL,
0.80 mmol) and iodoalkene 416 (145 mg, 0.53 mmol) in 1:1 CH2Cl2/
acetonitrile (10 mL) as described for the preparation of 5. After
workup and column chromatography (from hexanes to 9:1 hex-
anes/AcOEt) the title compound 17 was obtained as an oil: 233 mg
HMBC)
d 12.2 (CH3, C-18), 22.1 (CH2, C-6), 26.8 (CH2, C-19), 27.4
(CH2, C-16), 55.2 (CH2, C-21), 56.2 (CH2, C-5), 58.7 (CH2, C-3), 115.2
(CH, C-12), 117.9 (CH, C-9), 122.3 (CH, C-15), 123.4 (CH, C-10), 124.2
(CH, C-11), 126.3 (2 CH), 126.5 (C, C-7), 127.2 (CH, C-17), 129.2 (2
CH), 131.4 (C, C-8), 133.6 (CH), 136.5 (C, C-13), 137.0 (C, C-14), 139.1
(C, C-2), 139.3 (C), 142.1 (C, C-20); ESI-HRMS [MþH]þ calcd for
C25H27N2O2S 419.1788, found 419.1785.
4.3.9. 2,3,4,7-Tetrahydro-1(H)-3,5-([20]ethylprop[20]eno)azonino
[5,4-b]indole (20). From vinyl iodide 18. Operating as above, from
vinyl iodide 18 (90 mg, 0.22 mmol), tetracycle 20 was obtained after
column chromatography (from Et2O to 98:2 Et2O/diethylamine):
46 mg (75%).
(79%); 1H NMR (400 MHz)
d
0.74 (t, J¼7.2 Hz, 3H), 1.88 (q, J¼7.2 Hz,
2H), 2.70 (t, J¼5.6 Hz, 2H), 2.91 (t, J¼5.6 Hz, 2H), 3.10 (d, J¼6.4 Hz,
2H), 3.20 (s, 2H), 4.01 (d, J¼8 Hz, 2H), 5.65 (dt, J¼10.8 and 6.4 Hz,
1H), 5.89 (s, 1H), 6.05 (dt, J¼10.8 and 8 Hz, 1H), 7.18e7.27 (m, 2H),
7.34e7.41 (m, 3H), 7.50 (m, 1H), 7.75 (m, 2H), 8.13 (m, 1H); 13C NMR
From tetracycle 19. Mg (37 mg, 1.52 mmol) was added to a so-
lution of 19 (105 mg, 0.25 mmol) in MeOH (10 mL) and the resulting
mixture was stirred at rt for 4 h. Mg (34 mg, 1.40 mmol) was added
again and the stirring was continued at rt for 1 h. Workup as de-
scribed for the preparation of 16 and column chromatography
(from Et2O to 98:2 Et2O/diethylamine) gave the title compound 20
(100.5 MHz)
d 11.9 (CH3), 22.4 (CH2), 24.8 (CH2), 29.0 (CH2), 49.8
(CH2), 52.3 (CH2), 61.9 (CH2), 76.0 (CH), 114.8 (CH), 118.1 (CH), 120.4
(C), 123.2 (CH), 124.1 (CH), 126.2 (2 CH), 129.1 (2 CH), 129.2 (CH),
130.3 (C), 130.7 (CH), 133.4 (CH), 135.1 (C), 136.2 (C), 139.3 (C), 150.8
(C); ESI-HRMS [MþH]þ calcd for C25H28IN2O2S 547.0911, found
547.0909.
as an oil: 62 mg (88%); 1H NMR (400 MHz)
d
1.14 (t, J¼7.2 Hz, 3H),
2.15 (q, J¼7.2 Hz, 2H), 2.69 (ddd, J¼15.6, 10.8, and 3.2 Hz, 1H), 2.79
(dt, J¼14.8 and 3.2 Hz, 1H), 3.06 (dd, J¼14 and 3.6 Hz, 1H), 3.16 (d,
J¼12.4 Hz, 1H), 3.22 (dt, J¼15.6 and 3.2 Hz, 1H), 3.30 (d, J¼18.4 Hz,
1H), 3.34 (d, J¼12.4 Hz, 1H), 3.66 (ddd, J¼14.8, 10.8, and 3.2 Hz, 1H),
3.84 (d, J¼18.4 Hz, 1H), 3.89 (dd, J¼14 and 11.6 Hz, 1H), 5.61 (dd,
J¼11.6 and 3.6 Hz, 1H), 6.52 (s, 1H), 7.02e7.11 (m, 2H), 7.24 (d,
J¼7.2 Hz, 1H), 7.36 (dd, J¼7.2 and 1.2 Hz, 1H), 7.96 (br, 1H); 13C NMR
4.3.7. 3-[(Z)-2-Ethyl-3-iodo-2-propenyl]-2,3,4,7-tetrahydro-1(H)-
azonino[5,4-b]indole (18). A solution of carbamate 16 (248 mg,
0.79 mmol) in 1.2 M HCl in MeOH (10 mL) was stirred at rt for 12 h.
The reaction mixture was basified with 20% NH4OH and concen-
trated. The residue was partitioned between CH2Cl2 and H2O and
extracted with CH2Cl2. The organic extracts were dried and con-
centrated to give the crude secondary amine (151 mg). This mate-
rial was allowed to react with diisopropylethylamine (0.2 mL,
1.15 mmol) and iodoalkene 416 (240 mg, 0.87 mmol) 1:1 CH2Cl2/
acetonitrile (15 mL) as described above. After workup and column
chromatography (from hexanes to 4:1 hexanes/AcOEt) amine 18
(100.5 MHz)
d 12.3 (CH3), 20.6 (CH2), 26.9 (CH2), 29.4 (CH2), 54.4
(CH2), 57.2 (CH2), 59.7 (CH2), 110.3 (CH), 116.5 (C), 117.4 (CH), 119.2
(CH), 120.9 (CH), 122.7 (CH), 125.7 (CH), 130.0 (C), 134.3 (C), 136.1
(C), 136.3 (C), 141.8 (C); ESI-HRMS [MþH]þ calcd for C19H23N2
279.1856, found 279.1856.
was obtained as an oil: 142 mg (44%); 1H NMR (400 MHz)
d
0.93 (t,
4.3.10. NMR data of tetracycle 21$HCl. 1H NMR (400 MHz)
d 1.03 (t,
J¼7.2 Hz, 3H), 2.14 (qd, J¼7.2 and 0.8 Hz, 2H), 2.70 (t, J¼5.6 Hz, 2H),
2.98 (t, J¼5.6 Hz, 2H), 3.16 (d, J¼5.6 Hz, 2H), 3.23 (s, 2H), 3.80 (d,
J¼8 Hz, 2H), 5.63 (m, 1H), 5.75 (m, 1H), 5.98 (s, 1H), 7.03e7.12 (m,
2H), 7.25 (dd, J¼7.6 and 1.6 Hz, 1H), 7.46 (dd, J¼7.6 and 1.2 Hz, 1H),
J¼7.2 Hz, 3H), 2.01 (m, 2H), 2.74 (m, 1H), 2.84 (br s, 1H), 3.04 (dt,
J¼18.4 and 3 Hz, 1H), 3.21 (d, J¼16.8 Hz, 1H), 3.50 (m, 2H), 3.72 (d,
J¼13.2 Hz, 1H), 3.94 (d, J¼16.8 Hz, 1H), 4.05 (m, 1H), 4.25 (m, 1H),
5.61 (s, 1H), 5.84 (d, J¼12.8 Hz, 1H), 6.82 (d, J¼12.8 Hz, 1H),
7.30e7.66 (m, 8H), 8.29 (d, J¼8.4 Hz, 1H).
7.69 (br s, 1H); 13C NMR (100.5 MHz)
d 12.3 (CH3), 22.1 (CH2), 26.9
(CH2), 29.3 (CH2), 52.5 (CH2), 55.2 (CH2), 62.5 (CH2), 76.3 (CH), 110.1
(CH), 111.9 (C), 117.5 (CH), 118.9 (CH), 120.8 (CH), 127.4 (CH), 129.0
(C), 129.5 (CH), 132.6 (C), 134.5 (C), 150.6 (C); ESI-HRMS [MþH]þ
calcd for C19H24IN2 407.0979, found 407.0976.
4.3.11. NMR data of tetracycle 22. 1H NMR (400 MHz, assignment
aided by 1He1H COSY and HSQC)
d
0.91 (dd, J¼14.4 and 9.2 Hz, 1H,
6-H), 1.11 (t, J¼7.6 Hz, 3H, 18-H), 1.84 (d, J¼14 Hz, 1H, 3-H), 2.28 (m,
2H,19-H), 2.84 (d, J¼14 Hz,1H, 3-H), 3.05 (dd, J¼14.4 and 7.2 Hz,1H,
6-H), 3.15 (dd, J¼13.2 and 9.2 Hz, 1H, 5-H), 3.53 (dd, J¼13.2 and
7.2 Hz, 1H, 5-H), 6.28 (s, 1H, 21-H), 6.32 (s, 1H, 15-H), 6.79 (d,
J¼12 Hz, 1H, 16-H), 6.90 (d, J¼12 Hz, 1H, 17-H), 7.24e7.32 (m, 4H),
7.34e7.42 (m, 2H), 7.68 (dd, J¼7.5 and 1.2 Hz, 2H), 8.34 (d, J¼8.4 Hz,
1H, 12-H); 13C NMR (100.5 MHz, assignment aided by HSQC and
4.3.8. 8-(Phenylsulfonyl)-2,3,4,7-tetrahydro-1(H)-3,5-([20]ethylprop
[20]eno)azonino[5,4-b]indole (19). Pd2(dba)3 (28 mg, 0.03 mmol),
xantphos (35 mg, 0.06 mmol), and K2CO3 (125 mg, 0.9 mmol) were
added under Ar to a solution of vinyl iodide 17 (333 mg,
0.61 mmol) in 1:1 toluene/Et3N (50 mL) and the resulting mixture
was heated at 80 ꢂC for 1 h 30 min. The solvent was removed and
the residue was partitioned between CH2Cl2 and a saturated
aqueous NaHCO3 solution. The organic layer was dried and con-
centrated and the resulting residue was purified by column chro-
matography (from CH2Cl2 to 95:5 CH2Cl2/MeOH) to give tetracycle
19 as an oil: 217 mg (85%); 1H NMR (500 MHz, assignment aided by
HMBC)
d 15.4 (CH3, C-18), 25.5 (CH2, C-19), 27.7 (CH2, C-6), 42.8
(CH2, C-3), 57.1 (CH2, C-5), 110.7 (CH, C-16), 113.9 (C, C-14), 116.2
(CH, C-12), 118.1 (CH), 123.6 (C, C-20), 124.0 (C, C-7), 124.1 (CH),
125.1 (CH),126.7 (2 CH),128.7 (2 CH),131.0 (C, C-8),131.9 (CH, C-15),
133.1 (CH, C-21),133.4 (C, C-2),133.6 (CH), 134.2 (CH, C-17), 137.3 (C,
C-13), 138.6 (C); ESI-HRMS [MþH]þ calcd for C25H25N2O2S 417.1631,
found 417.1624.
1He1H COSY and HSQC)
d
0.98 (t, J¼7.5 Hz, 3H, 18-H), 2.00 (m, 2H,
19-H), 2.72 (ddd, J¼15.5, 11, and 4 Hz, 1H, 6-H), 2.91 (dt, J¼15 and
3.5 Hz, 1H, 5-H), 3.10 (dt, J¼15.5 and 3.5 Hz, 1H, 6-H), 3.16 (d,
J¼18 Hz, 1H, 21-H), 3.17 (d, J¼11.5 Hz, 1H, 3-H), 3.26 (d, J¼11.5 Hz,
1H, 3-H), 3.53 (ddd, J¼15, 11, and 3.5 Hz, 1H, 5-H), 3.75 (dd, J¼15.5
and 11 Hz, 1H, 16-H), 3.78 (d, J¼18 Hz, 1H, 21-H), 4.04 (dd, J¼15.5
4.3.12. Catalytic hydrogenation of 20. Method A. Diene 20 (43 mg,
0.15 mmol) dissolved in AcOEt (2.5 mL) was hydrogenated over
PtO2 (7 mg, 0.03 mmol) at rt for 1 h. The reaction mixture was
filtered through Celite, washing carefully with warm MeOH. The

M.-L. Bennasar et al. / Tetrahedron 69 (2013) 2534e2541
2541
filtrate was concentrated and the resulting residue was purified by
References and notes
column chromatography (Al2O3, from hexanes to 1:1 hexanes/
CH2Cl2) to give (ꢀ)-cleavamine20 (23, 17 mg, 40%) and (ꢀ)-dihy-
drocleavamine21 24 (10 mg, 23%). (ꢀ)-Cleavamine (23): 1H NMR
1. For general reviews, see: (a) Handbook of Metathesis; Grubbs, R. H., Ed.;
Wiley-VCH: Weinheim, Germany, 2003; Vol. 2; (b) Deiters, A.; Martin, S. F.
Chem. Rev. 2004, 104, 2199e2238.
€
(400 MHz, assignment aided by HSQC)
d
1.07 (t, J¼7.4 Hz, 3H, 18-H),
2. For general reviews, see: (a) Brase, S.; de Meijere, A. In Metal-catalyzed
Cross-coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: New York,
NY, 2004; pp 217e316; (b) Zeni, G.; Larock, R. C. Chem. Rev. 2006,106, 4644e4680.
1.90e2.01 (m, 2H,17-H), 2.04 (q, J¼7.4 Hz, 2H,19-H), 2.11 (br,1H,14-
H), 2.34e2.44 (m, 2H, 3-H and 5-H), 2.45 (m, 1H, 5-H), 2.60 (ddd,
J¼13.4, 7, and 0.8 Hz, 1H, 16-H), 2.69e2.79 (m, 2H, 3-H and 6-H),
2.80 (m, 1H, 6-H), 3.06 (d, J¼15.6 Hz, 1H, 21-H), 3.16 (d, J¼15.6 Hz,
1H, 21-H), 3.73 (dd, J¼13.4 and 12.4 Hz, 1H, 16-H), 5.29 (d, J¼4 Hz,
1H, 15-H), 7.04e7.13 (m, 2H, 10-H and 11-H), 7.28 (dm, J¼7.2 Hz, 1H,
12-H), 7.48 (dd, J¼7.2 and 1.6 Hz, 1H, 9-H), 7.78 (br, 1H, NH); 13C
ꢀ
3. (a) Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Synlett 2008, 667e670; (b)
ꢀ
Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Tetrahedron 2012, 68, 4641e4648.
ꢀ
4. (a) Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Chem. Commun. 2009,
ꢀ
3372e3374; (b) Bennasar, M.-L.; Zulaica, E.; Sole, D.; Roca, T.; García-Díaz, D.;
Alonso, S. J. Org. Chem. 2009, 74, 8359e8368.
5. (a) Rawal, V. H.; Michoud, C. Tetrahedron Lett. 1991, 32, 1695e1698; (b) Rawal,
V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc. 1993, 115, 3030e3031; (c)
Martin, D. B. C.; Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131, 3472e3473.
NMR (125.7 MHz, assignment aided by HSQC)
d 12.6 (CH3, C-18),
ꢀ
6. (a) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685e2686; (b) Sole, D.;
22.5 (CH2, C-16), 26.1 (CH2, C-6), 27.6 (CH2, C-19), 34.1 (CH2, C-17),
35.3 (CH, C-14), 53.5 (CH2, C-3), 53.9 (CH2, C-5), 55.1 (CH2, C-21),
109.8 (CH, C-12), 109.9 (C, C-7), 117.8 (CH, C-9), 118.7 (CH, C-10),
120.6 (CH, C-11), 122.4 (CH, C-15), 128.7 (C, C-8), 135.4 (C, C-13),
139.4 (C, C-2), 140.8 (C, C-20); ESI-HRMS [MþH]þ calcd for
C19H25N2 281.2012, found 281.2016. (ꢀ)-Dihydrocleavamine (24):
ꢀ
Bonjoch, J.; García-Rubio, S.; Peidro, E.; Bosch, J. Chem.dEur. J. 2000, 6,
655e665; (c) Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt,
M.; Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324e9337; (d) Mori, M.;
Nakanishi, M.; Kahishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 9801e9807;
(e) Martin, D. B. C.; Nguyen, L. Q.; Vanderwal, C. D. J. Org. Chem. 2012, 77, 17e46.
7. Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem.
Soc. 2008, 130, 5368e5377.
8. For reviews, see: (a) Cordell, G. A. In Indoles, The Monoterpenoid Indole Alkaloids;
Saxton, J. E., Ed.; Wiley: New York, NY, 1983; Vol. 25, Part 4, Chapter 10; (b)
Saxton, J. E. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; Wiley:
Chichester, UK, 1994; Supplement to Vol. 25, Part 4, Chapter 10.
9. Sundberg, R. J.; Smith, S. Q. In The Alkaloids; Cordell, G. A., Ed.; Academics:
Amsterdam, The Netherlands, 2002; Vol. 59, Chapter 2.
1H NMR (400 MHz)
d
0.88 (t, J¼7.6 Hz, 3H), 1.31 (m, 2H), 1.41e1.63
(m, 3H), 1.75 (m, 2H), 1.91 (dddd, J¼12.4, 11.6, 6.4, and 1.2 Hz, 1H),
2.17 (dd, J¼12 and 6 Hz, 1H), 2.26 (d, J¼12 Hz, 1H), 2.33 (m, 1H),
2.40e2.52 (m, 2H), 2.62 (d, J¼7.2 Hz, 1H), 2.65 (d, J¼7.2 Hz, 1H),
2.82e2.88 (m, 2H), 3.70 (t, J¼12.8 Hz, 1H), 7.04e7.12 (m, 2H), 7.28
(dd, J¼8 and 1.2 Hz, 1H), 7.46 (dd, J¼8 and 1.2 Hz, 1H), 7.78 (br, 1H);
10. The Alkaloids; Brossi, A., Ed.Suffness, M., Ed.; Academic: San Diego, CA, 1990;
Vol. 37.
11. Mangeney, P.; Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y.; Potier, P. J. Org.
Chem. 1979, 44, 3765e3768.
13C NMR (125.7 MHz)
d 11.7 (CH3), 21.1 (CH2), 26.3 (CH2), 28.7 (CH2),
31.2 (CH2), 32.7 (CH), 33.7 (CH2), 35.1 (CH), 51.7 (CH2), 52.2 (CH2),
59.0 (CH2), 109.9 (CH), 110.1 (C), 117.8 (CH), 118.8 (CH), 120.6 (CH),
128.5 (C), 135.5 (C), 138.8 (C); ESI-HRMS [MþH]þ calcd for C19H27N2
283.2169, found 283.2166.
Method B. Diene 20 (62 mg, 0.22 mmol) in AcOEt (3.5 mL) was
hydrogenated over PtO2 (13 mg, 0.057 mmol) at rt for 5 h. Workup
and column chromatography as above gave 24: 27 mg (43%).
12. For reviews on the synthesis of medium-sized rings by RCM, see: (a) Maier, M.
E. Angew. Chem., Int. Ed. 2000, 39, 2073e2077; (b) Yet, L. Chem. Rev. 2000, 100,
2963e3007; (c) Michaut, A.; Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45,
5740e5750.
13. For example, see: (a) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett. 1998, 39,
4139e4142; (b) Enders, D.; Lenzen, A.; Backes, M.; Janeck, C.; Catlin, K.; Lannou,
M.-I.; Runsink, J.; Raabe, G. J. Org. Chem. 2005, 70, 10538e10551; (c) Ribelin, T.
P.; Judd, A. S.; Akritopoulou-Zanze, I.; Henry, R. F.; Cross, J. L.; Whittern, D. N.;
Djuric, S. W. Org. Lett. 2007, 9, 5119e5122.
14. For a preliminary communication of part of this work, see: Bennasar, M.-L.;
ꢀ
Sole, D.; Zulaica, E.; Alonso, S. Org. Lett. 2011, 13, 2042e2045.
ꢀ
15. Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Tetrahedron 2007, 63, 861e866.
Acknowledgements
16. Zhang, Y.; Herndon, J. W. Org. Lett. 2003, 5, 2043e2045.
17. Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.; Salvino, J.; Arison, B.;
Cichy, M. A.; Spoors, P. G.; Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith,
A. B., III; Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.; Freidinger, R.
M.; Cascieri, M. R.; Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550e12568.
18. Forexamples in the literature, see: (a) Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org.
Lett. 2003, 5, 89e92; (b) Schwartz, K. D.; White, J. D. Org. Lett. 2011, 13, 248e251.
19. The structure of 21 could be determined by 1H NMR analysis of the corre-
sponding hydrochloride.
20. For NMR data of cleavamine, see: (a) Kutney, J. P.; Brown, R.; Piers, E. Can. J.
Chem. 1965, 43, 1545e1552; (b) Imanishi, T.; Nakai, A.; Yagi, N.; Hanaoka, M.
Chem. Pharm. Bull. 1981, 29, 901e903; (c) Wenkert, E.; Hagaman, E. W.;
Kunesch, N.; Wang, N.-Y. Helv. Chim. Acta 1976, 59, 2711e2723.
We thank the Ministerio de Economía y Competitividad, Spain,
for financial support (project CTQ2009-07175) and the University
of Barcelona for a grant to S.A.
Supplementary data
Copies of 1H and 13C NMR spectra of all new compounds. Sup-
plementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2013.01.064.
21. For NMR data of (þ)-20R-dihydrocleavamine, see: van Beek, T. A.; Verpoorte, R.;
Svendsen, A. B. Tetrahedron 1984, 40, 737e748.