Stereoselective synthesis of tetracyclic indolines via gold-catalyzed cascade cyclization reactions

Article abstract of DOI:10.1039/c1cc12328a

A reliable synthetic route to fused polycyclic indolines is documented by the development of a stereoselective gold catalyzed cascade cyclization of indole propargylic alcohols.

Full text of DOI:10.1039/c1cc12328a

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COMMUNICATION
Stereoselective synthesis of tetracyclic indolines via gold-catalyzed
cascade cyclization reactionsw
Gianpiero Cera, Pasquale Crispino, Magda Monari and Marco Bandini*
Received 21st April 2011, Accepted 10th May 2011
DOI: 10.1039/c1cc12328a
A reliable synthetic route to fused polycyclic indolines is
documented by the development of a stereoselective gold catalyzed
cascade cyclization of indole propargylic alcohols.
Indoline alkaloids are prominent molecular motifs in naturally
occurring compounds displaying distinct pharmacological
properties.1 These compounds are commonly constituted by
polycyclic fused molecular architectures featuring quaternary
stereocenters,2 and represent stimulating/nontrivial synthetic
exercises for organic chemists. Although cascade methodologies
are rising to prominence,3 elaborate multi-step synthetic
sequences are still normally required for the preparation
of stereochemically defined indoline alkaloids.4 As a consequence,
it is not surprising to record a growing need for selective
and sustainable procedures for the preparation of densely
functionalized polycyclic indolines.
Fig. 1 Working plan for the synthesis of polycyclic fused indolines
(in red nucleophilic sites, in blue electrophilic sites).
source, solvent and temperature was then undertaken and the
results are collected in Table 1.
Early screening experiments with different gold sources
revealed that cationic gold(I) catalysts displayed greater
competence with respect to [Au(III)] analogues (entries 1 and 2),
in providing the tetracyclic fused indoline 2a (yields up to 33%).
This trend can be tentatively ascribed to poisoning phenomena
exerted by the aminic nitrogen atom of 2a on the most electro-
philic [Au(III)] species. Among the gold(I) p-acids scrutinized
(entries 3–7), the well-defined silver-free complex 3b (5 mol%)13
was elected as the catalyst of choice providing 2a with high
5-exo-dig regiochemistry (vide infra for X-ray analysis) and an
excellent diastereomeric ratio (yield = 74%, dr 4 50 : 1, entry 7).
Among the solvents examined (MeOH, toluene, MeNO2 and
DCM, entries 7–10), CH2Cl2 proved to be the reaction media
of choice. Moreover, partial decomposition of the starting
compound was recorded under forced conditions (toluene, reflux,
entry 11) and higher loadings of 3b (i.e. 10 mol%) did not
significantly impact the isolated yield of 2a (80%, entry 12,
Table 1). Then, the roles of the counterion as well as the
phosphine ligand were further investigated through experimental
controls carried out with preformed gold complexes [PPh3AuCl]
and [dppf(AuCl)2] in the presence of AgSbF6 (entries 13 and 14).
Here, while the entry 13 proved unambiguously the superiority of
SbF6 with respect to OTf counterion in terms of chemical yield
(entry 13 vs. 3), dinuclear cationic gold species [dppf(AuSbF6)2]
led to 2a in lower extent (yield = 31%). Finally, it is worth
noting that, at a difference with the recent report by Wang and
coworkers,9 the presence of activating EWG groups on the
N(1)-atom was not mandatory in our methodology.
In relation to our recent interests in the stereoselective gold
catalyzed functionalization of indole cores,5,6 we reasoned
that the functional group compatibility and fine-tunability,
commonly associated with gold catalyzed transformations
of unsaturated hydrocarbons,7 would constitute desirable
requirements to implement atom/step economical synthetic
shortcuts to structurally complex indoline alkaloids.
The present working hypothesis relied on the use of readily
available unprotected (NH)-indole propargylic alcohols A that
when subjected to electrophilic activation of the C–C triple bond
by gold species8 could enter into a Friedel–Crafts alkylation/
iminium trapping reactive sequence (Fig. 1).9 A main strength of
the methodology relies on the widely accessible chemical diversity
(i.e. tetracyclic dihydropyranylindolines B and corresponding
furoindolines C),10 due to the interplay of structural design of
the acyclic precursor (n = 1,2) with the high regioselectivity
featured by the gold assisted hydroindolination of alkynes.11,12
At the outset of the investigation, we identified in the
unprotected (NH)-indole alcohol 1a, a readily accessible
model substrate comprising the molecular requisites exemplified
by compound A. A survey of reaction conditions namely: gold
Dipartimento di Chimica ‘‘G. Ciamician’’, Alma Mater
`
Studiorum—Universita di Bologna, via Selmi 2, Bologna I-40126,
Italy. E-mail: marco.bandini@unibo.it; Tel: +39 (0)51-2099751
w Electronic supplementary information (ESI) available: CCDC
814206 (2c) and 814207 (5a). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1cc12328a
The substrate scope was then ascertained by subjecting
a range of indole propargylic alcohols (1b–j) to the cascade
c
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Table 1 Catalyst optimization for the gold catalyzed tandem cyclization
of 1aa
electron-withdrawing groups located at the C(5)- and C(6)-
positions of the indolyl ring (entries 6–9).
Contrarily, indole compounds carrying electron-donating
groups (i.e. 1d,e) proved to be more reluctant toward the
cascade cyclization, however by increasing the catalyst loading
to 10 mol%, indolines 2d,e were isolated in high chemical yields
(70–86%, entries 4 and 5). Moreover, also 2-methylindole
derivative 1j proved to be a suitable precursor for compound
2j, with the simultaneous formation of two consecutive quaternary
stereocenters in a diastereomerically defined manner (yield =
59%, entry 10).
Subsequently, the scope of the synthetic method was
expanded further, by highlighting its compatibility to indolyl
precursors 4a–d, derived from the corresponding tryptamine
derivatives.
Entry
[Au]
[Ag]
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
AuCl3
AuCl3
[PPh3AuCl]
[(PPh3Au)3O]BF4
[AuIMes]Cl
3a
3b
3b
3b
3b
3b
3b
—
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
MeOH
MeNO2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
10
33
45
72
55
60
74
72
61
63
56
80
68
31
AgOTf
AgOTf
—
AgOTf
—
—
—
—
—
—
It is worth noting that, by subjecting these alcohols to optimal
ring-closing conditions (3b, CH2Cl2, rt, 16 h) tetracyclic
polyfunctionalized furoindolines 5a–d (7-endo-dig pathway) were
isolated in moderate to good yields (52–76%) as single diastereo-
isomers (Fig. 2). Also in this case, both EWGs and EDGs were
efficiently supported by the gold catalysis. Interestingly, opposite
regiochemistry, with respect to alcohols 1 was recorded. This
inversion can be tentatively rationalized in terms of intrinsic
molecular requisites of the precursors. As a matter of fact, while
the 6-endo-dig mechanism seems not structurally accessible for
compounds 1-type, due to the limited length of the side chain,
the introduction of longer and more flexible side arms (i.e.
compounds 4)14 opens access to the 7-endo-dig cyclization
pathway, as previously reported in the hydroindolination of
unfunctionalized internal alkynes.11b
9
10
11c
12d
13
14
—
AgSbF6
AgSbF6
[PPh3AuCl]
[dppf(AuCl)2]
a
All the reactions were carried out under nitrogen conditions at room
b
temperature, unless otherwise specified. Isolated yield after flash
chromatography. In all cases, compound 2a was obtained as a single
diastereoisomer (1H-NMR and LC-analysis). Under reflux. 10 mol%
of the catalyst was used at rt. IMes = 1,3-bis(2,4,6-trimethylphenyl)-
imidazol-2-ylidene.
c
d
The molecular architectures of dihydropyranyl indolines and
NTs-furoindolines were unambiguously determined by single
crystal X-ray diffraction studies on compounds 2c and 5a (Fig. 3).
Mechanistically, although detailed experimental evidences are
still elusive, a tentative hypothesis is depicted in Scheme 1. Here,
the initial Au(I)-assisted electrophilic activation of the triple bond
can trigger a Friedel–Crafts-type alkylation of the indole ring,
with the formation of spirovinyl-gold intermediates D.15,16 Then,
the regioselective functionalization of the C(3)-position of the
indole nucleus could provide an avenue toward the trapping of
the incipient iminium group by the hydroxyl group. Finally, the
protodeauration step would result into the desired tetracyclic
compounds 2 or 5.17
Table 2 Scope of the diastereoselective gold catalyzed synthesis of
indolines 2a
Entry
R1/R2/R3
E
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
H/H/H (1b)
H/H/H (1c)
H/H/H (1c)
H/Me/H (1d)
H/OMe/H (1e)
H/Cl/H (1f)
H/Cl/H (1g)
H/Br/H (1h)
Cl/H/H (1i)
H/H/Me (1j)
CO2Me
CO2tBu
CO2tBu
CO2Et
CO2Et
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
2b
2c
2c
2d
2e
2f
2g
2h
2i
75
70
81c
70c
86c
75
75
75
78
59
2j
a
All the reactions were carried out under nitrogen conditions at room
b
temperature. Isolated yield after flash chromatography. In all cases,
compounds 2 were isolated as a single diastereoisomer (1H-NMR and
c
LC-analysis). In the presence of 10 mol% of the catalyst.
ring-closing reaction under the most favourable experimental
conditions (Table 2). Firstly, the malonyl tethering unit did
not exhibit a marked influence on the final chemical output,
and the corresponding dihydropyranyl indolines 2b,c were
isolated in comparable yields (70–81%, entries 1–3). Good
yields (up to 78%) were also obtained in the presence of
Fig.
2
Tetracyclic furoindolines derived from NTs tryptamine
precursors 4a–d.
c
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4 (a) T. Sunazuka, K. Yoshida, N. Kojima, T. Shirahata, T. Hirose,
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Fig. 3 Solid state structure of fused tetracyclic compounds 2c (left)
and 5a (right).w
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Scheme 1 Tentative mechanistic sketch.
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In conclusion, we have documented an unprecedented atom/
step economic synthesis of fused tetracyclic N(H)-free
pyranyl indolines and furoindolines, via gold-catalyzed cascade
cyclization. High levels of chemo-, regio- and diastereoselectivity
were obtained for a range of densely functionalized compounds.
Further studies into the development of an enantioselective
variant of the protocol along with a detailed mechanistic
investigation are currently underway in our laboratory.
Acknowledgement is made to Progetto FIRB ‘‘Futuro in
Ricerca’’ Innovative sustainable synthetic methodologies for
C–H activation processes, (MIUR, Rome), Universita di
Bologna.
9 For a complementary gold-catalyzed synthetic approach based on
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14 The role of the tethering group in the overall regiochemical output
was ruled out by subjecting to optimal cyclization conditions a
4-type compound featuring the malonyl unit in the sidearm. Here,
although in lower extent (yield = 22%), only the compound
derived from 7-endo-dig cyclization was recorded.
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D via
ring-opening of cyclopropyl gold carbene intermediates (ref. 11b)
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7803–7805 7805