Enantioselective gold-catalyzed synthesis of polycyclic indolines

Article abstract of DOI:10.1021/ol300297t

The synthesis of architecturally complex polycyclic fused indolines is achieved in a chemo-, regio-, and stereodefined manner, via an enantioselective gold-catalyzed cascade hydroindolination/iminium trapping synthetic sequence. Highly functionalized tetr

Full text of DOI:10.1021/ol300297t

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1350–1353
Enantioselective Gold-Catalyzed
Synthesis of Polycyclic Indolines
Gianpiero Cera,† Michel Chiarucci,† Andrea Mazzanti,‡ Michele Mancinelli,‡ and
Marco Bandini*,†
Department of Chemistry, “G. Ciamician”, Alma Mater Studiorum ꢀ University of
Bologna, via Selmi 2, 40126 Bologna, Italy, and Department of Organic Chemistry
“A. Mangini”, Alma Mater Studiorum ꢀ University of Bologna, viale Risorgimento 4,
40136 Bologna, Italy
marco.bandini@unibo.it
Received February 6, 2012
ABSTRACT
The synthesis of architecturally complex polycyclic fused indolines is achieved in a chemo-, regio-, and stereodefined manner, via
an enantioselective gold-catalyzed cascade hydroindolination/iminium trapping synthetic sequence. Highly functionalized tetra-
cyclic fused furoindolines (2) and dihydropyranylindolines (4) are synthesized in moderate to good yields and enantiomeric excesses
of up to 87%.
Enantioselective gold catalysis continues to inspire and
influence developments in organic synthesis,1 providing
reliable solutions to the current demand for selective and
sustainable synthetic methodologies.2 The stereoselective
manipulation of unfunctionalized unsaturated hydrocarbons
has greatly benefited from the rediscovery of asymmetric
gold catalysis, with applications in the synthesis of complex
molecular architectures.3
The proven pharmacological activity of indole alka-
loids,4 combined with their challenging molecular skele-
tons, concurs to define this class of polycyclic fused indolyl
compounds as intriguing synthetic exercises for organic
chemists.5 In this segment, although catalytic asymmetric
methodologies have already provided reliable solutions,6
there is still an urgent need for sustainable and enantiose-
lective protocols for their preparation.
† Department of Chemistry “G. Ciamician”, University of Bologna.
‡ Department of Organic Chemistry “A. Mangini”, University of Bologna.
(1) (a) Widenhoefer, R. A. Chem.;Eur. J. 2008, 14, 5382. (b) Gorin,
D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351. (c)
Sengupta, S.; Shi, X. Chem.Cat.Chem. 2010, 2, 609. (d) Hashmi, A. S. K.;
Hubbert, C. Angew. Chem., Int. Ed. 2010, 49, 1010. (e) Pradal, A.;
Toullec, P. Y.; Michelet, V. Synthesis 2011, 1501.
(4) (a) Takano, S.; Ogasawara, K. Alkaloids 1989, 36, 225. (b)
Fattorusso, E.; Taglialatela Scafati, O. Modern Alkaloids; Wiley-VCH:
(2) For general reviews on gold-catalyzed organic transformations,
see: (a) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2005, 44, 6990. (b)
Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45,
7896. (c) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (d) Hashmi,
ꢀ
Weinheim, 2008. (c) Ruiz Sanchis, P.; Savina, S. A.; Albericio, F.; Alvarez,
M. A. Chem.;Eur. J. 2011, 17, 1388.
(5) (a) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46,
5488. (b) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003.
(6) For representative examples of catalytic enantioseletive synthesis
of indolines via cascade reactions, see: (a) Matsuura, T.; Overman, L. E.;
Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500. (b) Austin, J. F.; Kim,
S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5482. (c) Trost, B. M.; Quancard, J. J. Am. Chem.
Soc. 2006, 128, 6314. (d) Jones, S. B.; Simmons, B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2009, 131, 13606. (e) Repka, L. M.; Ni, J.; Reisman,
S. E. J. Am. Chem. Soc. 2010, 132, 14418. (f) Wu, Q.-F.; He, H.; Liu,
W.-B.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418. (g) Jones, S. B.;
Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475,
183. (h) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012,
51, 1680.
€
A. S. K. Chem. Rev. 2007, 107, 3180. (e) Furstner, A.; Davies, O. D.
Angew. Chem., Int. Ed. 2007, 46, 4310. (f) Li, Z.; Brouwer, C.; He, C.
ꢀ
ꢀ~
Chem. Rev. 2008, 108, 3239. (g) Jimenez-Nunez, E.; Echavarren, A. M.
Chem. Rev. 2008, 108, 3326. (h) Shen, H. C. Tetrahedron 2008, 64, 3885.
(i) Skouta, R.; Li, C.-J. Tetrahedron 2008, 64, 4917. (j) Arcadi, A. Chem.
Rev. 2008, 108, 3266. (k) Bongers, N.; Krause, N. Angew. Chem., Int. Ed.
2008, 47, 2178. (l) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075.
(m) Shapiro, N. D.; Toste, F. D. Synlett 2010, 675. (n) Corma, A.; Leyva-
ꢀ
Perez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657. (o) Bandini, M.
Chem. Soc. Rev. 2011, 40, 1358.
(3) (a) Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37,
€
1766. (b) Furstner, A. Chem. Soc. Rev. 2009, 38, 3208. (c) Rudolph, M.;
Hashmi, A. S. K. Chem. Soc. Rev. 2012, DOI: 10.1039/c1cs15279c.
r
10.1021/ol300297t
Published on Web 02/15/2012
2012 American Chemical Society

Our recent interests in the stereoselective manipulation
of indolyl cores7 drove our attention toward the exploita-
tion of the well-established regioselective gold-catalyzed
hydroindolination of alkynes8 as a rapid and direct access
to polycyclic fused indolines. Interestingly, despite the
large amount of effort in this research line,9 to the best of
our knowledge no examples of enantioselective variants
have been reported so far.10
In this communication we describe an unprecedented
enantioselective gold-catalyzed cascade reaction of func-
tionalized propargylic alcohols11 leading to N(1)-unpro-
tected indolines carrying additional 6/5-fused (A) and
5/7-fused (B) ring connections.
Hydroarylation of the carbonꢀcarbon triple bond and
subsequent iminium trapping, operated by the alkenyl-
gold intermediates,12 constitute the hypothetical reaction
machinery (Figure 1).13
At the outset of the present investigation we envisioned
that, as the overall stereochemistry of the final product
(A or B) is essentially ruled by the initial gold-triggered
regioselective hydroindolination of the triple bond, the use
of chiral gold complexes could theoretically open access to
the unprecedented enantioselective gold-catalyzed syn-
thesis of indolines carrying all-carbon quaternary stereo-
centers at the C(3) position.
Aiming to discover the optimal reaction parameters, we
first underwent a screening of reaction conditions (namely,
ligands, solvent, gold counterions, and temperature) by
selecting 1a as a readily available and synthetically flexible
model acyclic precursor (Table 1).
Chart 1. Chiral Ligands Tested in the Optimization of the
Catalytic System
Figure 1. Working hypothesis: enantioselective synthesis of
polycyclic indolines via gold-catalyzed cascade reactions
(merely speculative stereochemical descriptors are reported).
(7) (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9533. (b) Bandini, M.; Eichholzer, A.; Gualandi, A.; Quinto, T.; Savoia, D.
Chem.Cat.Chem. 2010, 2, 661. (c) Bandini, M.; Gualandi, A.; Monari, M.;
Romaniello, A.; Savoia, D.; Tragni, M. J. Organomet. Chem. 2011, 696, 338.
(8) (a) Li, Z.; Shi, Z.; He, C. J. Organomet. Chem. 2005, 690, 5049. (b)
Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 1105. (c)
Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.;Eur. J. 2007, 13,
ꢀ
~ ꢀ
1358. (d) Barluenga, J.; Fernandez, A.; Rodrıguez, F.; Fananas, F. J.
´
J. Organomet. Chem. 2009, 694, 546.
(9) (a) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351,
1517. (b) Verniest, G.; England, D.; De Kimpe, N.; Padwa, A. Tetra-
hedron 2010, 66, 1496. (c) Hirano, K.; Inaba, Y.; Watanabe, T.; Oishi, S.;
Fujii, N.; Ohno, H. Adv. Synth. Catal. 2010, 352, 368. (d) Gruit, M.;
Pews-Davtyan, A.; Beller, M. Org. Biomol. Chem. 2011, 9, 1148.
(10) For recent examples of a gold-catalyzed enantioselective cascade
reaction involving ene-ino cyclizations, see: (a) Munoz, M. P.; Adrio, J.;
Carretero, J. C.; Echavarren, A. E. Organometallics 2005, 24, 1293. (b)
A range of chiral C2-symmetrical bis-phosphine ligands
(L1ꢀ6, 5 mol %, Chart 1) were initially tested in the
cascade reaction by preparing in situ the corresponding
cationic binuclear gold complexes of the general formula
L(AuSbF6)2 (entries 1ꢀ6, Table 1).14
^
Chao, C.-M.; Vitale, M. R.; Toullec, P. Y.; Genet, J.-P.; Michelet, V.
Remarkably, in all cases 5-exo-dig regiochemistry was
obtained exclusively, and among the ligands tested, (R)-
xylyl-binap ligand L3 provided 2a in higher stereoinduc-
tion (ee = 56%) and moderate yield (65%, entry 3). The
role of the gold counterion was then evaluated in the
presence of L3 (entries 7ꢀ11). Here, while the use of
para-NO2-benzoate (pNBn) did not promote the reaction
at all, the addition of AgOTf and AgBF4 provided 2a in
comparable yield (60%) and ee up to 74% (entry 9).
Gratifyingly, by lowering the temperature at 0 °C and in
the presence of 4 A MS, (6aR,11bR)-2a was isolated in
Chem.;Eur. J. 2009, 15, 1319. (c) Sethofer, S. G.; Mayer, T.; Toste,
F. D. J. Am. Chem. Soc. 2010, 132, 8276. (d) Martı
Garcı
´
nez, A.; Garcı
ꢀ
´ ´ ´
a, P.; Fernandez-Rodrıguez, M. A.; Rodrıguez, F.; Sans, R.
´
a-
Angew. Chem., Int. Ed. 2010, 49, 4633.
(11) For representative examples of gold-catalyzed manipulation of
propargylic alcohols, see: (a) Muzart, J. Tetrahedron 2008, 64, 5815. (b)
Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550. See also:
Biannic, B.; Aponick, A. Eur. J. Org. Chem. 2011, 6605.
(12) (a) Liu, L.-P.; Xu, B.; Mashuta, M. S.; Hammond, G. B. J. Am.
Chem. Soc. 2008, 130, 17642. (b) Hashmi, A. S. K.; Schuster, A. M.;
Rominger, F. Angew. Chem., Int. Ed. 2009, 48, 8247. (c) Weber, D.;
ꢀ
Tarselli, M. A.; Gagne, M. R. Angew. Chem., Int. Ed. 2010, 48, 5733. (d)
Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232. (e) Hashmi,
A. S. K.; Ramamurthi, T. D.; Rominger, F. Adv. Synth. Catal. 2010, 352,
971. (f) Hashmi, A. S. K.; Schuster, A. M.; Gaillard, S.; Cavallo, L.;
Poater, A.; Nolan, S. P. Organometallics 2011, 30, 6328.
(13) For a preliminary communication addressing a diastereoselec-
tive methodology, see: (a) Cera, G.; Crispino, P.; Monari, M.; Bandini,
M. Chem. Commun. 2011, 47, 7803. See also: (b) Liu, Y.; Xu, W.; Wang,
X. Org. Lett. 2010, 12, 1448. (c) Noey, E. L.; Wang, X.; Houk, K. N.
J. Org. Chem. 2011, 76, 3477.
(14) Chiral mononuclear gold complexes based on phosphoramidite
ligands were also tested, furnishing 2a only in traces. For related
€
€
references, see: Teller, H.; Flugge, S.; Goddard, R.; Furstner, A. Angew.
Chem., Int. Ed. 2010, 49, 1949.
Org. Lett., Vol. 14, No. 5, 2012
1351

Table 1. Enantioselective Synthesis of the Dihydropyranylin-
doline 2aa
Table 2. Scope of the Reactiona
yield
(%)b
ee
(%)c
entry
1
R/R1/R2
yield
(%)b
ee
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
tBu/H/H
Me/H/H
Et/Br/H
Et/Cl/H
65
60
75
70
50
58
67
51
87
76
81
75
76
83
84
77
entry
L
AgX
(%)c
1
(R,R)-L1
(S)-L2
AgSbF6
“
21
46 (þ)
20 (ꢀ)
56 (ꢀ)
14 (ꢀ)
0
2
26
3
(R)-L3
(S)-L4
“
65
Et/MeO/H
Me/Cl/H
Et/H/Cl
4
“
36
1g
1h
1i
5
(R)-L5
(S)-L6
“
61
6
“
65
17 (ꢀ)
72 (ꢀ)
27 (ꢀ)
74 (ꢀ)
70 (ꢀ)
--
tBu/MeO/H
7
(R)-L3
(R)-L3
(R)-L3
(R)-L3
(R)-L3
(R)-L3
(R)-L3
(R)-L3(AuCl)2
AgOTf
AgNTf2
AgBF4
AgPF6
AgpNBn
AgBF4
AgBF4
AgBF4
59
a All the reactions were carried out under a nitrogen atmosphere with
anhydrous solvents. Compounds 2 were always isolated as a single
diastereoisomer. b Isolated yields after flash chromatography. c Deter-
mined by HPLC analysis with a chiral column.
8
80
9
60
10
11
12d
13e
14d,f
70
traces
89
86 (ꢀ)
82 (ꢀ)
84 (ꢀ)
conditions providing the corresponding cyclized com-
pounds 2f,i with ee up to 77%. Analogously, 5- and
6-halo-derivatives (2dꢀe,gꢀh) led to the tetracyclic dihy-
dropyranylindolines with enantiomeric excesses ranked
between 75% and 84%.
72
82
a All the reactions were carried out under a nitrogen atmosphere with
anhydrous solvents. 2a was always isolated as a single diastereoisomer.
The precatalytic cationic dinuclear complexes were synthesized in situ,
unless otherwise specified. b Isolated yields after flash chromatography.
c Determined by HPLC analysis with chiral column. d Reaction at 0 °C,
4 h, in the presence of activated 4 A MS. e In the presence of activated 5 A
MS. f Preformed gold complex was utilized. L1, (R,R)-binaphane; L2,
(S)-xylyl-phanephos; L3, (R)-xylyl-binap; L4, (S)-DTBM-segphos; L5,
(R)-xylyl-SDP; L6, (S)-MeO-biphep; pNBn, para-NO2-benzoate.
Finally, the scope of the reaction was expanded further
proving the competence of readily accessible alcohols 3 as
acyclic precursors in the present gold-catalyzed process. In
particular, tryptamine derivatives 3a,b underwent cycliza-
tion via a preferential 7-endo-dig regiochemical pathway
leading to tetracyclic furoindolines 4, carrying a fused aza-
substituted unsaturated seven-membered cycle. Interest-
ingly, optimal results were recorded by subjecting
model substrates 3a,b to reaction conditions involv-
ing (S)-DTBM-segphos(AuOTf)2 as the chiral catalyst
(5 mol %) and benzene as the solvent (see Supporting
Information for further details). In particular, diaste-
reomerically pure furoindolines (7aR,12bS)-4a,b were
isolated in satisfying yields and enantiomeric excesses
up to 85% (Scheme 1).
89% yield with 86% ee (entry 12). Finally, the use of
activated 5 A MS (entry 13) or the preformed L3(AuCl)2
(entry 14) complex did not lead to substantial variations
(ee up to 84%) with respect to the optimal reaction
parameters.
Encouraged by the results obtained in the standard
cascade reaction assays, we verified the generality of the
method by subjecting a series of N(H)-free indole pro-
pargylic alcohols 1bꢀi to standard cyclization conditions,
and the results are summarized in Table 2. In the presence
of 5 mol % of (R)-[L3(AuBF4)2], satisfactory yields
(50ꢀ75%) were obtained over a range of indole substi-
tutions as well as malonyl tethering units. In all cases,
corresponding tetracyclicindolines2bꢀi wereisolated with
excellent chemo- and diastereoselectivity (>50:1). In par-
ticular, the nature of the “R” group did not impact the
stereochemical profile of the reaction course, with a slight
increase in enantioselection (ee = 87%), when bulky
(tBu)2-malonyl derivative 1b was utilized (entry 1).
Moreover, both electron-withdrawing (i.e., halogen
atoms) and electron-donating (i.e., MeO, Me) substituents
were tolerated equally well in different positions (C(5)
and C(6)) of the indole periphery. In particular, 5-OMe
substituted alcohols 1f,i reacted smoothly under optimal
Absolute configurations of the indolines 2b and 4a were
unambiguously determined by simulation of their electron-
ic circular dichroism spectra and [R]D values by means of
the TD-DFT approach.15
Scheme 1. Enantioselective Synthesis of Tetracyclic Furoindo-
lines 4, via 7-endo-dig Cyclization Pathway
1352
Org. Lett., Vol. 14, No. 5, 2012

for 2b showed very good agreement with the experimental
spectra of the major enantiomers (Figure 2). Also the
calculated [R]D values matched well with the experimental
signs and values, thus enforcing the reliability of the
assignment.
In conclusion, we have documented an unprecedented
enantioselective cascade reaction for the preparation of
tetracyclic fused indolines via gold-catalyzed hydroindoli-
nation of propargylic alcohols.
The ready availability of the acyclic precursors, the mild
reaction conditions, and the good levels of regio-, diastereo-,
and enantioselectivity nominate the protocol as a rapid
entry to stereodefined polycyclic indoline alkaloids.
Acknowledgment. Acknowledgment is made to Proget-
to FIRB “Futuro in Ricerca” Innovative sustainable syn-
thetic methodologies for CꢀH activation processes (MIUR,
Rome) and University of Bologna (RFO funds).
Figure 2. TD-DFT simulations of the electronic circular dichro-
ism spectra of compounds 2b and 4a. The black traces corre-
spond to the experimental spectra. The purple lines show the
simulations obtained assuming the 7aR,12bS configuration for
4a and the 6aR,11bR configuration for 2b.
Supporting Information Available. Experimental de-
tails, characterization data, NMR spectra, chiral HPLC
chromatograms, optimization catalytic system, and de-
tails on the absolute configuration determination. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The ECD spectra calculated for the 7aR,12bS absolute
configuration of 4a and for the 6aR,11bR configuration
(15) See the Supporting Information for the discussion of the abso-
lute configuration assignment. For reviews, see: (a) Bringmann, G.;
Bruhn, T.; Maksimenka, K.; Hemberger, Y. Eur. J. Org. Chem. 2009,
2717. (b) Crawford, T. D.; Tam, M. C.; Abrams, M. L. J. Chem. Phys. A
2007, 111, 12057.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
1353