An easy entry to optically active spiroindolinones: Chiral Bronsted acid-catalysed Pictet-Spengler reactions of isatins

Article abstract of DOI:10.1002/adsc.201100050

The first catalytic asymmetric Pictet-Spengler reaction of isatins is presented. BINOL-derived phosphoric acids were found to be competent catalysts for this transformation, giving challenging spirooxindole structures bearing a quaternary stereocentre with generally good results. The 1,2,3,4-tetrahydro- β-carboline products (spiroindolinones) are the core of some newly discovered anti-malarial agents.

Full text of DOI:10.1002/adsc.201100050

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DOI: 10.1002/adsc.201100050
An Easy Entry to Optically Active Spiroindolinones: Chiral
Brønsted Acid-Catalysed Pictet–Spengler Reactions of Isatins
Sara Duce,a,b Fabio Pesciaioli,a Lucia Gramigna,a Luca Bernardi,a,*
Andrea Mazzanti,a Alfredo Ricci,a Giuseppe Bartoli,a and Giorgio Bencivennia,*
a
Department of Organic Chemistry “A. Mangini”, University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Fax : (+39)-051-209-3654; phone: (+39)-051-209-3631; e-mail: luca.bernardi2@unibo.it or giorgio.bencivenni2@unibo.it
Departamento de Quꢀmica Orgꢁnica, Universidad Autꢂnoma de Madrid, Cantoblanco, 28049, Madrid, Spain
b
Received: January 20, 2011; Published online: April 12, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100050.
Abstract: The first catalytic asymmetric Pictet–
Spengler reaction of isatins is presented. BINOL-
derived phosphoric acids were found to be compe-
tent catalysts for this transformation, giving chal-
lenging spirooxindole structures bearing a quaterna-
ry stereocentre with generally good results. The
1,2,3,4-tetrahydro-b-carboline products (spiroindol-
the natural spirotryprostatins,[7] or to all-carbon cyclo-
alkyl-spirooxindoles.[8a–d] We disclose herein a direct
catalytic enantioselective access to tetrahydro-b-car-
boline spirooxindoles (spiroindolinones) 4. These
unique spirooxindole architectures are assembled by
means of a chiral Brønsted acid[9]-catalysed Pictet–
Spengler[10] reaction between tryptamines 2 and isa-
tins 3 (Scheme 1), thus giving the first access to this
class of compounds in an enantioselective manner.
Remarkably, tetrahydro-b-carboline spirooxindoles of
type 4 are the core of some potent anti-malarial
agents showing very good pharmacokinetic properties,
recently discovered by intensive high throughput
screening processes.[4]
ACHTUNGTRENNUNGinones) are the core of some newly discovered anti-
malarial agents.
Keywords: asymmetric catalysis; Brønsted acids; or-
ganocatalysis; Pictet–Spengler reaction; spirooxin-
doles
We started our optimisation (Table 1) by studying
the reaction of tryptamine 2a with isatin 3a under the
catalysis of several (S)-BINOL derived phosphoric
Spirooxindole is a privileged scaffold in medicinal acids 1a–f with different substituents at the 3 and 3’
chemistry. Taking inspiration from bioactive com- positions (Table 1 entries 1–6).[9,11] THF was chosen as
pounds isolated from natural sources, many spirooxin- reaction medium to ensure solubilisation of isatin 3a.
dole derivatives have been prepared in recent times. After 20 h at 408C, all reactions worked quite well
A number of these compounds shows outstanding from a conversion standpoint. However, all the
biological profiles.[1] Some of these molecules are Brønsted acids 1 tested furnished poor enantioselec-
indeed very promising drug candidates for the treat- tivity with the only exception of 1f[12] that allowed us
ment of, e.g., cancer,[2] tuberculosis,[3] and malaria.[4]
However, the molecular and stereochemical complex-
ity that identifies this class of compounds still repre-
sents a significant synthetic challenge.[1a–c,5] The con-
struction of a highly hindered, strained spirocyclic
quaternary chiral centre is in fact not a trivial task, es-
pecially in an enantioselective fashion.[6]
In the last years, catalytic asymmetric cycloaddi-
tion[7] and cascade[8] reactions have proved to be
amongst the most powerful approaches for the direct
enantioselective assembly of the spirooxindole frame-
work, starting from commercial or readily available
compounds. These reports are however mostly limited
to pyrrolidin-3-yl-spirooxindole motives resembling tween tryptamines 2 and isatins 3.
Scheme 1. Catalytic asymmetric Pictet–Spengler reaction be-
860
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Adv. Synth. Catal. 2011, 353, 860 – 864

An Easy Entry to Optically Active Spiroindolinones
Table 1. Optimisation of the reaction conditions for the asymmetric Pictet-Spengler reaction of tryptamine 2a with isatin
3a.[a]
Entry
R
Solvent/[2a]0
Conv [%][b]
ee [%][c]
1
2
3
4
Ph (1a)
biphenyl (1b)
4-NO2-C6H4 (1c)
SiPh3 (1d)
3,5-(CF3)2-C6H3 (1e)
2,4,6-(i-Pr)3-C6H2 (1f)
1f
1f
1f
1f
1f
1f
1f
1f
1f
THF/0.2M
THF/0.2M
THF/0.2M
THF/0.2M
THF/0.2M
THF/0.2M
THF/0.2M
CH2Cl2/0.2M
MeCN/0.1M
EtOH/0.2M
DMF/0.2M
DMF/0.5M
DMF/1.0M
DMF/0.1M
DMF/0.2M
64
56
54
40
58
full
50
full
90
full
full
89
<5
<5
<5
<5
40
86
90
54
82
5
6
7[d]
8
9
10
11
12
13
14
15[f]
70
92 (99)[e]
90
90
full
full
80
92
88
[a]
Unless otherwise specified, the reactions were performed at 408C on a 0.05 mmol scale (2a:3a=1:1), using 10 mol% of
catalyst.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR analysis of the crude mixture, refers to both ketimine and isatin 3a.
Determined by HPLC analysis on chiral stationary phases.
Reaction performed at room temperature for 65 h.
After a single crystallisation.
5 mol% of (S)-1f was used.
to obtain the desired compound 4a in 86% enantio- the stereochemical outcome (Table 1, entries 11–14).
meric excess (Table 1, entry 6). The same reaction Decreasing catalyst loading to 5 mol% gave slightly
conducted at room temperature furnished slightly diminished enantioselectivity (Table 1, entry 15).
better enantiocontrol, yet careful analysis of the Worthy of note is that essentially enantiopure 4a
crude mixture revealed the presence of the ketimine could be obtained after
intermediate even after 65 h (Table 1, entry 7). This (Table 1, entry 11).
a single crystallisation
observation prompted us to evaluate the feasibility of
With optimal conditions at hand we focussed our
the reaction in other solvents (Table 1, entries 8– attention on the scope of the reaction between vari-
11).[13] We found that DMF was the solvent of choice ous tryptamines 2a–d and isatins 3a–k for the synthe-
with regard to reactivity and enantioselectivity. The sis of enantioenriched spiroindolinones 4a–n
reaction proceeded smoothly in this medium afford- (Table 2). Variation of the isatin 3 structure was very
ing product 4a in 92% ee (Table 1, entry 11). To addi- well tolerated by the catalytic system. Different isa-
tionally optimise the reaction conditions, the use of tins 3a–g, bearing substituents with different electron-
some additives was explored, without finding any ben- ic or steric properties at the various positions of the
eficial effect.[13] The reaction revealed to be negatively aryl ring, all gave the corresponding adducts 4a–g
influenced also by an increase in reagent concentra- with good results in terms of yields and enantioselec-
tion, although a more diluted solution did not affect tivities (Table 2, entries 1–7). Substitution with differ-
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Sara Duce et al.
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Table 2. Brønsted acid-catalysed Pictet–Spengler reaction of tryptamines 2a–d with isatins 3a–k.[a]
Entry
2
R
R1
3
R2
R3
R4
4 Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2d
H
H
H
H
H
H
H
H
H
H
H
Br
MeO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
Me
All
Bn
Me
Me
H
H
F
H
H
Me
MeO
Me
H
H
H
H
H
F
4a 85
4b 87
4c 80
4d 80
4e 81
4f 75
4g 81
4h 74
4i 80
4j 68
4k 97
4l 90
4m 87
4n 74
92
89
90[d]
90[d]
76
Cl
Me
H
H
H
H
H
H
H
H
H
90
84
95
9
92[d]
73[d]
90[d]
78[d]
90
10
11
12[e]
13
14
3j
3k
3h
3a
3a
Me
H
H
H
H
71
[a]
Unless otherwise specified, the reactions were performed at 408C on a 0.1 mmol scale (2:3=1:1) with 10 mol% of (S)-1f.
Reaction time 18–48 h.
Isolated yield after chromatography on silica gel.
Determined by HPLC analysis on chiral stationary phases.
Refers to the opposite enantiomer. (R)-1f was used as the catalyst.
Reaction performed at 608C.
[b]
[c]
[d]
[e]
ent groups at the isatin nitrogen was also possible. An enantioselectivity (71% ee vs. 92% ee), with same Si-
effect of the steric hindrance of this substituent was face selectivity.[15] Also in this case, the absolute con-
however observed, as the relatively small methyl and figuration of 4n was determined from its ECD spec-
allyl groups in isatins 3h, i, k gave the corresponding trum.[13] This result might suggest that a Lewis base
À
adducts 4h, i, k with comparable, or even better, re- interaction with the indole N H is not operative. An
sults than the parent unsubstituted isatin 3a, whereas eventual interaction between the Lewis base moiety
with the more hindered 1-benzyl isatin 3j a decrease of the catalyst (P=O) with the proton at the 2-position
in the enantioselectivity was observed (Table 2, en- of the indole nucleus might instead be envisioned, as-
tries 8–11). Variation of tryptamine structure was then sisting the hydrogen transfer process,[16] resulting in
explored, indicating the possibility of using indoles the transition state depicted in Figure 1. Steric con-
differently substituted at the 5-position, such as the straints and bi-coordination of the (S)-BINOL-de-
serotonine derivative 2c and the corresponding bromo rived catalyst 1f force the activated ketimine into the
derivative 2b (Table 2, entries 12 and 13). The re- conformation shown, thus giving addition at the Si-
quirement of a higher reaction temperature (608C) face. A possible interaction with the isatin NH can in-
for the latter less reactive bromo derivative 2b caused stead be excluded, given the very similar behaviour of
a slight decrease in stereoselctivity. Tryptamine 2d isatins 3h–k, bearing different alkyl substituents at ni-
bearing a methyl substituent at the indole nitrogen trogen, with the parent isatin 3a.
could also be employed (Table 2, entry 14).
Finally, the surprising tolerance of this reaction to
The absolute configuration of compound 4a was de- small amounts of water is remarkable and deserves
termined as S by simulation of the electronic circular some comments. During the optimisation process,[13]
dichroism spectra (ECD) and [a]D values.[13] In many the same results in terms of catalyst activity and selec-
organocatalytic asymmetric processes involving the tivity were in fact observed with reagent grade or dry
indole nucleus, coordination of the indole NH by a solvents, with or without different desiccants (i.e., mo-
Lewis base moiety is considered to be crucial for reac- lecular sieves), in sharp contrast with most phosphoric
tivity and enantioselectivity.[14] However, in this asym- acid 1-catalyzed asymmetric transformations.[9,10,12,15,17]
metric Pictet–Spengler reaction, the corresponding N- Even more striking, the addition of increasing quanti-
methylindole tryptamine 2d gave similar, albeit lower, ties of water to the mixture did not compromise the
862
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Adv. Synth. Catal. 2011, 353, 860 – 864

An Easy Entry to Optically Active Spiroindolinones
1:1 n-hexane:acetone) to provide the desired spiroindoli-
nones 4.
Acknowledgements
We acknowledge financial support from “Stereoselezione in
Chimica Organica, Metodologie e Applicazioni” 2009. S. D.
thanks Universidad Autꢀnoma de Madrid and Comunidad
Autꢀnoma de Madrid for a fellowship. We are grateful to G.
Bergonzini for the preparation of (S)-1f catalyst, and to Dr.
M. Mancinelli for recording ECD spectra.
Figure 1. Proposed transition state.
References
enantioselectivity, although conversion was lowered.
The high polarity of the optimum solvent (DMF),
able in principle to accept hydrogen bonds, is also
noteworthy. Taken together, these data highlight the
unique properties of the large tris(isopropyl)phenyl
substituents of catalyst 1f, which have recently al-
lowed the development of the first asymmetric phos-
phoric acid-catalyzed reaction in water.[18] A possible
interpretation ascribes to the hindered aryl groups of
phosphoric acid 1f the ability to wrap the active site
of the catalyst in a hydrophobic pocket, “protecting”
the ketimine complex depicted in Figure 1 from exter-
nal hydrogen bond donors or acceptors.
In summary, the first catalytic asymmetric Pictet–
Spengler reaction using isatins as carbonyl compo-
nents was developed, giving easy access to optically
active spiroindolinones starting from readily available
catalysts and starting materials. The tolerance to
moisture gives a further practical dimension to this
transformation, which furnishes enantioenriched
structures of great interest for their biological proper-
ties, being the core of some newly discovered antima-
larial agents.
[1] Overviews: a) C. V. Galliford, K. A. Scheidt, Angew.
Chem. 2007, 119, 8902–8912; Angew. Chem. Int. Ed.
2007, 46, 8748–8758; b) B. M. Trost, M. K. Brennan,
Synthesis 2009, 3003–3025; c) C. Marti, E. Carreira,
Eur. J. Org. Chem. 2003, 2209–2219. See also: d) A.
Claesson, M.-M. Swahn, O.-G. Berge, Spirooxindole de-
rivatives that act as analgesics, U.S. Patent 6,774,132,
2004; e) A. Fensome, R. Bendler, J. Cohen, M. A. Col-
lins, V. A. Mackner, L. L. Miller, J. W. Ullrich, R. Win-
neker, J. Wrobel, P. Zhang, Z. Zhang, Y. Zhu, Bioorg.
Med. Chem. Lett. 2002, 12, 3487–3490; f) A. Fensome,
W. R. Adams, A. L. Adams, T. J. Berrodin, J. Cohen, C.
Huselton, A. Illenberger, J. C. Kern, V. A. Hudak,
M. A. Marella, E. G. Melenski, C. C. McComas, C. A.
Mugford, O. D. Slayden, M. Yudt, Z. Zhang, P. Zhang,
Y. Zhu, R. C. Winneker, J. E. Wrobel, J. Med. Chem.
2008, 51, 1861–1873.
[2] a) K. Ding, Y. Lu, Z. Nikolovska-Coleska, S. Qiu, Y.
Ding, W. Gao, J. Stuckey, K. Krajewski, P. P. Roller, Y.
Tomita, D. A. Parrish, J. R. Deschamps, S. Wang, J.
Am. Chem. Soc. 2005, 127, 10130–10131; b) S. Shang-
ary, D. Qin, D. McEachern, M. Liu, R. S. Miller, S. Qiu,
Z. Nikolovska-Coleska, K. Ding, G. Wang, J. Chen, D.
Bernard, J. Zhang, Y. Lu, Q. Gu , R. B. Shah, K. J.
Pienta, X. Ling, S. Kang, M. Guo, Y. Sun, D. Yang, S.
Wang, Proc. Natl. Acad. Sci. USA 2008, 105, 3933–
3938; c) M. M.-C. Lo, C. S. Neumann, S. Nagayama,
E. O. Perlstein, S. L. Schreiber, J. Am. Chem. Soc. 2004,
126, 16077–16086.
Experimental Section
[3] V. V. Vintonyak, K. Warburg, H. Kruse, S. Grimme, K.
Hꢅbel, D. Rauth, H. Waldmann, Angew. Chem. 2010,
122, 6038–6041; Angew. Chem. Int. Ed. 2010, 49, 5902–
5905.
General Procedure
To a test-tube equipped with a magnetic stirring bar were
sequentially added the tryptamine 2a–d (0.10 mmol), cata-
lyst (S)-1f (7.5 mg, 0.010 mmol, 10 mol%), DMF (reagent
grade, 500 mL) and the isatin 3a–k (0.10 mmol). The test-
tube was capped and placed in an oil bath at 408C. The mix-
ture was then vigorously stirred at the same temperature for
18–48 h, with no precautions to exclude moisture or air. The
reaction mixture was then cooled to room temperature, di-
luted with Et2O (5 mL) and washed with 10% aqueous
Na2CO3 (2ꢄ5 mL). The organic layer was washed with brine
and dried over MgSO4. After filtration, the solvent was
evaporated under reduced pressure giving a brown residue,
which was purified by chromatography on silica gel (3:1 to
[4] a) M. Rottmann, Case McNamara, B. K. S. Yeung,
M. C. S. Lee, B. Zou, B. Russell, P. Seitz, D. M. Plouffe,
N. V. Dharia, J. Tan, S. B. Cohen, K. R. Spencer, G. E.
Gonzꢁlez-Pꢁez, S. B. Lakshminarayana, A. Goh, R. Su-
wanarusk, T. Jegla, E. K. Schmitt, H.-P. Beck, R. Brun,
F. Nosten, L. Renia, V. Dartois, T. H. Keller, D. A.
Fidock, E. A. Winzeler, T. Diagana, Science 2010, 329,
1175–1180; b) S. H. Ang, P. Krastel, S. Y. Leong, L. J.
Tan, W. L. J. Wong, B. K. S. Yeung, B. Zou, (Novartis
AG), U.S. Patent 2009/0275560A1, 2009; c) J.-J. Liu, Z.
Zhang, (Hoffmann-La Roche AG), Spiroindolinone de-
rivatives: PCT Int. Appl. WO 2008/055812, 2008; d) Q.
Adv. Synth. Catal. 2011, 353, 860 – 864
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
863

Sara Duce et al.
COMMUNICATIONS
Ding, J.-J. Liu, Z. Zhang, PCT Int. Appl. WO 2007/
104714, 2007.
[5] F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010,
352, 1381–1407.
A. M. Seayad, B. List, J. Am. Chem. Soc. 2006, 128,
1086–1087. For overviews over indole chemistry in
asymmetric catalysis, also covering Pictet–Spengler re-
actions, see: j) M. Bandini, A. Eicholtzer, Angew.
Chem. 2009, 121, 9786–9824; Angew. Chem. Int. Ed.
2009, 48, 9608–9644; k) G. Bartoli, G. Bencivenni, R.
Dalpozzo, Chem. Soc. Rev. 2010, 39, 4449–4465;
l) T. B. Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108,
2903–2915; m) E. Marquꢆs-Lꢂpez, R. P. Herrera, M.
Christmann, Nat. Prod. Rep. 2010, 27, 1138–1167.
[11] a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew.
Chem. 2004, 116, 1592–1594; Angew. Chem. Int. Ed.
2004, 43, 1566–1568; b) D. Uraguchi, M. Terada, J.
Am. Chem. Soc. 2004, 126, 5356–5357.
[6] a) M. Bella, T. Gasperi, Synthesis 2009, 1583–1614;
b) P. G. Cozzi, R. Hilgraf, R. Zimmermann, Eur. J. Org.
Chem. 2007, 5969–5994; c) B. M. Trost, C. Jiang, Syn-
thesis 2006, 369–396; d) E. J. Corey, A. Guzman-Perez,
Angew. Chem. 1998, 110, 402–415; Angew. Chem. Int.
Ed. 1998, 37, 388–401.
[7] a) A. P. Antonchick, C. Gerding-Reimers, M. Catarinel-
la, M. Schꢅrmann, H. Preut, S. Zieger, D. Rauh, H.
Waldmann, Nature Chem. 2010, 2, 735–740; b) X.-H.
Chen, Q. Wei, S.-W. Luo, H. Xiao, L.-Z. Gong, J. Am.
Chem. Soc. 2009, 131, 13819–13825.
[8] a) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi,
F. Pesciaioli, M.-P. Song, G. Bartoli, P. Melchiorre,
Angew. Chem. 2009, 121, 7336–7339; Angew. Chem.
Int. Ed. 2009, 48, 7200–7203; b) K. Jiang, Z.-J. Jia, S.
Chen, L. Wu, Y.-C. Chen, Chem. Eur. J. 2010, 16,
2852–2856; c) K. Jiang, Z.-J. Jia, X. Yin, L. Wu, Y.-C.
Chen, Org. Lett. 2010, 12, 2766–2769; d) X. Jiang, Y.
Cao, Y. Wang, L. Liu, F. Shen, R. Wang, J. Am. Chem.
Soc. 2010, 132, 15328–15333; e) X. Cheng, S. Vellalath,
R. Goddard, B. List, J. Am. Chem. Soc. 2008, 130,
15786–15787. For a related approach to spirobenzofur-
anones: f) C. Cassani, X. Tian, E. C. Escudero-Adꢁn, P.
Melchiorre, Chem. Commun. 2011, 47, 233–235.
[9] Reviews: a) T. Akiyama, Chem. Rev. 2007, 107, 5744–
5758; b) A. Doyle, E. N. Jacobsen, Chem. Rev. 2007,
107, 5713–5743; c) T. Akiyama, J. Itoh, K. Fuchibe,
Adv. Synth. Catal. 2006, 348, 999–1010; d) M. Terada,
Chem. Commun. 2008, 35, 4097–4112; e) M. Terada,
Synthesis 2010, 1929–1982; f) S.-L. You, Q. Cai, M.
Zeng, Chem. Soc. Rev. 2009, 38, 2190–2201; g) A.
Zamfir, S. Schenker, M. Freund, S. B. Tsogoeva, Org.
Biomol. Chem. 2010, 8, 5262–5276; h) Z. Zhang, P.
Schreiner, Chem. Soc. Rev. 2009, 38, 1187–1198.
[10] a) A. Pictet, T. Spengler, Ber. Dtsch. Chem. Ges. 1911,
44, 2030–2036; b) E. D: Cox, J. M. Cook, Chem. Rev.
1995, 95, 1797–1842. Organocatalytic enantioselective
Pictet-Spengler reactions: c) M. J. Wanner, R. N. S. van
der Haas, K. R. de Cuba, J. H. van Maarseveen, H.
Hiemstra, Angew. Chem. 2007, 119, 7629–7631; Angew.
Chem. Int. Ed. 2007, 46, 7485–7487; d) M. S. Taylor,
E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558–
10559; e) N. V. Sewgobind, M. J. Wanner, S. Ingemann,
R. de Gelder, J. H. Maarseveen, H. Hiemstra, J. Org.
Chem. 2008, 73, 6405–6408; f) M. E. Muratore, C. A.
Holloway, A. W. Pilling, R. I. Storer, G. Trevitt, D. J.
Dixon, J. Am. Chem. Soc. 2009, 131, 10796–10797;
g) I. T. Raheem, P. S. Thiara, E. A. Paterson, E. N. Ja-
cobsen, J. Am. Chem. Soc. 2007, 129, 13404–13405;
h) C. A. Holloway, M. E. Muratore, R. I. Storer, D. J.
Dixon, Org. Lett. 2010, 12, 4720–4723; i) J. Seayad,
[12] a) S. Hoffmann, A. M. Seayad, B. List, Angew. Chem.
2005, 117, 7590–7593; Angew. Chem. Int. Ed. 2005, 44,
7424–7427; b) G. Adair, S. Mukherjee, B. List, Aldri-
chimica Acta 2008, 41, 31–39.
[13] See the Supporting Information for details.
[14] See, for example: a) R. P. Herrera, V. Sgarzani, L. Ber-
nardi, A. Ricci, Angew. Chem. 2005, 117, 6734–6737;
Angew. Chem. Int. Ed. 2005, 44, 6576–6579; b) C.
Gioia, A. Hauville, L. Bernardi, F. Fini, A. Ricci,
Angew. Chem. 2008, 120, 9376–9379; Angew. Chem.
Int. Ed. 2008, 47, 9236–9239; c) J. Itoh, K. Fuchibe, T.
Akiyama, Angew. Chem. 2008, 120, 4080–4082; Angew.
Chem. Int. Ed. 2008, 47, 4016–4018; for computational
proof of this interaction, see: d) C. Zheng, Y.-F. Sheng,
Y.-X. Li, S.-L. You, Tetrahedron 2010, 66, 2875–2880;
e) L. Simon, J. M. Goodman, J. Org. Chem. 2010, 75,
589–597.
[15] For examples of chiral phosphoric acid-catalyzed asym-
metric reactions involving N-alkylindoles and pyrroles,
see: a) M. Rueping, B. J. Nachtsheim, S. A. Moreth, M.
Bolte, Angew. Chem. 2008, 120, 603–606; Angew.
Chem. Int. Ed. 2008, 47, 593–596; b) M. Zeng, Q.
Kang, Q.-L. He, S.-L. You, Adv. Synth. Catal. 2008,
350, 2169–2173; c) G. B. Rowland, E. B. Rowland, Y.
Liang, J. A. Perman, J. C. Antilla, Org. Lett. 2007, 9,
2609–2611; d) G. Li, G. B. Rowland, E. B. Rowland,
J. C. Antilla, Org. Lett. 2007, 9, 4065–4068.
[16] In Pictet–Spengler reactions of dopamine taking place
in biological settings, isotopic effects have shown that
proton-transfer process causing re-aromatisation, assist-
ed by a carboxylate enzyme basic residue, is partially
rate-determining in the overall reaction. See: L. Y. P.
Luk, S. Bunn, D. K. Liscombe, P. J. Facchini, M. E.
Tanner, Biochemistry 2007, 46, 10153–10161.
[17] For our own experience: a) G. Bergonzini, L. Grami-
gna, A. Mazzanti, M. Fochi, L. Bernardi, A. Ricci,
Chem. Commun. 2010, 46, 327–329; b) L. Bernardi, M.
Comes-Franchini, M. Fochi, V. Leo, A. Mazzanti, A.
Ricci, Adv. Synth. Catal. 2010, 352, 3399–3406.
[18] M. Rueping, T. Theissmann, Chem. Sci. 2010, 1, 473–
476.
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