Enantioselective Gold-Catalyzed Pictet-Spengler Reaction

Article abstract of DOI:10.1021/acs.orglett.9b03656

Cationic chiral Au(I) complexes catalyze asymmetric Pictet-Spengler reactions between tryptamines and arylaldehydes. The resulting tetrahydro-β-carbolines are obtained with wide functional group tolerance in high yield and with high enantioselectivities (

Full text of DOI:10.1021/acs.orglett.9b03656

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Gold-Catalyzed Pictet−Spengler Reaction
Nicolas Glinsky-Olivier,† Shengwen Yang,‡,§ Pascal Retailleau,† Vincent Gandon,*,‡,§
and Xavier Guinchard*,†
†
́
́
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite Paris-Sud, Universite Paris-Saclay, 1 avenue de la
Terrasse, Gif-sur-Yvette 91198, France
‡
́
́
́
́
Institut de Chimie Moleculaire et des Materiaux d’Orsay, CNRS UMR 8182, Universite Paris-Sud, Universite Paris-Saclay,
̂
Batiment 420, Orsay CEDEX 91405, France
§
́
Laboratoire de Chimie Moleculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, IP Paris, route de Saclay, Palaiseau CEDEX
91128, France
S
* Supporting Information
ABSTRACT: Cationic chiral Au(I) complexes catalyze asymmetric Pictet−Spengler reactions between tryptamines and
arylaldehydes. The resulting tetrahydro-β-carbolines are obtained with wide functional group tolerance in high yield and with
high enantioselectivities (up to 95%). Aldehydes bearing polar or protic functions are well tolerated. The reaction features a
hitherto unknown C2-auration of the indole as the key step, supported by density functional theory calculations.
biological activities and are currently available as drugs or
drug candidates.3b
he Pictet−Spengler reaction is the acid-catalyzed
Tcondensation of β-arylethylamines with aldehydes,
leading to tetrahydroisoquinolines1 or tetrahydro-β-carbolines
(TH-β-Cs)2 through the intermediacy of an iminium. With
more than a century of intense research, the Pictet−Spengler
reaction has now proved to be one of the most efficient and
reliable method for the synthesis of tetrahydro-β-carbolines, a
major class of heterocyclic compounds (Scheme 1).3 Some of
these derivatives are natural products, such as (R)-tryptargine
or strictosidine. Numerous compounds embedding this
structural unit are endowed with wide and interesting
Numerous efforts have been made by synthetic chemists to
control the absolute stereochemistry of C1.4 Enantioselective
approaches to tetrahydro-β-carbolines include the reduction of
dihydro-β-carbolines, using Ru or Rh chiral complexes via
asymmetric transfer hydrogenation reactions5 or biocatalyzed
reductions.6 However, the Pictet−Spengler reaction is
unarguably the leading synthetic strategy for the efficient
synthesis of chiral tetrahydro-β-carbolines.7 Beyond diaster-
eoselective Pictet−Spengler reactions, enantioselective variants
of the reaction can be catalyzed by Pictet−Spenglerase
enzymes,8 or by Brønsted acid organocatalysis.9 Jacobsen,
Seidel, List, and Hiemstra have developed elegant enantiose-
lective Pictet−Spengler reactions using chiral thioureas10 or
chiral phosphoric acids11 as catalysts, which have found
numerous applications in total synthesis.11d,12 Each of these
methods has its strengths and weaknesses in the nature of the
aldehyde used, the substituting pattern of the tryptamine, or
the electronic environment around the indole ring. However,
in the context of such an important synthetic transformation,
one must note that no enantioselective strategies using
organometallic catalysis have been reported.
Scheme 1. Structure and Natural Occurrence of Tetrahydro-
β-carbolines
In the course of a project aiming at the synthesis of
polycyclic indole derivatives,13 we extensively used the chiral
phosphoric-acid-catalyzed Pictet−Spengler reaction to prepare
key tetrahydro-β-carboline moieties that were cyclized to more
Received: October 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03656
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Letter
complex polycyclic compounds using palladium13a,b or gold
catalysis.13c,d During the study of the carboamination of N-
allyltetrahydro-β-carbolines to alkynes, we incidentally identi-
fied Au(I) complexes as efficient catalysts for the Pictet−
Spengler reaction and developed a sequence combining this
step with the carboamination cyclization (Scheme 2, eq 1).13d
a
Table 1. Optimization of the Reaction
b
c
entry
1
catalyst
yield (%)
ee
Scheme 2. Gold-Catalyzed Synthesis of TH-β-Cs
d
1
1a
1a
1a
1b
1c
1d
1e
1f
1f
1f
1f
1f
Ph3PAuNTf2 4
AgNTf2
3aa, 90
3aa, 0
2
3
4
5
6
7
8
9
10
11
12
13
L1(AuCl)2
L1(AuCl)2
L1(AuCl)2
L1(AuCl)2
L1(AuCl)2
L1(AuCl)2
L2(AuCl)2
L3(AuCl)2
L4(AuCl)2
L5(AuCl)2
L6(AuCl)2
3aa, 99
3ba, 90
3ca, 50
3da, 88
3ea, 80
3fa, 84
3fa, 82
3fa, 32
75
57
52
74
75
83
91
80
93
79
78
3fa, quant.
3fa, 82
1f
3fa, 99
Precedence in the field was shown using achiral Au(I)14 or
Au(III)15 complexes, but it was not clear from the literature
the role that gold complexes could play in such a reaction,
traditionally catalyzed by acids. In this Letter, we demonstrate
that chiral Au(I) complexes efficiently catalyze enantioselective
Pictet−Spengler reactions (Scheme 2, eq 2) and report our
efforts in determining the scope of the reaction and
understanding its mechanism.
We initiated this work by establishing a suitable catalytic
system. After we checked that tryptamine itself did not react
under these conditions,16 we prepared a series of tryptamines 1
with diverse substituents to test under different catalytic
conditions. We first engaged N-benzyl tryptamine 1a in a
Pictet−Spengler reaction with benzaldehyde 2a in the presence
of the Gagosz’s catalyst Ph3PAuNTf2 417 in dichloromethane
(DCM) and molecular sieves,18 leading to the expected
product 3aa in 90% yield (Table 1, entry 1). By anticipation
that the use of chiral neutral Au(I) complexes necessitates a
silver activation, we checked that the silver salt AgNTf2 was not
catalytically active (entry 2). We next selected the DTBM−
MeO−BIPHEP chiral ligand providing the digold complex
L1(AuCl)2 (3 mol %), using AgNTf2 (5.8 mol %) as a chloride
abstractor and screened tryptamines 1a−f (entries 3−8).
Tryptamines 1b and 1c bearing an allyl and a naphthylmethyl
group led to moderate enantiomeric excesses (ee’s) (entries 4
and 5), whereas all other tryptamines substituted by a benzyl-
type protecting group led to an average 75% ee in good yield
(entries 3 and 6−8). The best enantiomeric excess was
obtained with a CH2Mes group, leading to 83% ee (entry 8).
We further screened a series of chiral diphosphines (entries 9−
13)19 that identified (DM)−SEGPHOS L4 as the best chiral
ligand, delivering a 93% ee (entry 11).20
a
Reactions were run using 1 (0.1 mmol) and 2a (0.2 mmol) in DCM
b
c
(1 mL) at rt. Isolated yields. Determined by chiral high-
performance liquid chromatography (HPLC). No silver salt added.
d
aryl substituents (3fb−ff). Suitable crystals of compound 3fe
allowed us to determine the absolute configuration of the
stereogenic center as R.21 The presence of an electron-
donating group led to a drop in the ee to 73% in 3fg. Aldehyde
2h, including a boronic acid function, led to 1fh with 88% ee.
The reaction performed from terephthalaldehyde 2i led to 3fi
with an excellent 95% ee and in 86% yield. Remarkably, there
was no trace of difunctionalization despite the presence of a
second aldehyde function. Finally, against all odds, the reaction
tolerated the highly electrophilic nitrone function, reputed
reactive toward Au(I) complexes.22 The corresponding
tetrahydro-β-carboline 3fj was isolated in excellent yield and
with 72% ee. Ortho-substituted aromatic aldehydes were next
screened. Halide substituents were found to be compatible
with the established conditions, although a better ee was
obtained with the less sterically demanding fluorine atom,
leading to 3fl in 87% ee. On the contrary, mesomeric electron-
withdrawing groups such as cyanide or nitro resulted in lower
ee’s. Aldehydes substituted at the meta position by either
halogens or trifluoromethyl groups resulted in excellent ee’s,
>90% for 3fo−fq. Despite a significant drop of the ee to 61%,
the reaction was compatible with an unprotected phenol
function, leading to compound 3fr in 92% yield. When the
reaction was performed with a dialdehyde (m-phthalaldehyde
2s), 3fs was isolated with an excellent 95% ee with, again, no
The optimal conditions were then applied to a series of
aromatic aldehydes using L4(AuCl)2 as the precatalyst and 1f
as the tryptamine partner on a 0.3 mmol scale (Scheme 3).
Benzaldehyde afforded 3fa in 97% yield and with 92% ee.
Aldehydes bearing a substituent in the para position led to
excellent results with a good tolerance toward halide, alkyl, and
B
DOI: 10.1021/acs.orglett.9b03656
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Letter
a
Scheme 3. Scope of Aldehydes in the Gold-Catalyzed Enantioselective Pictet−Spengler Reaction with Tryptamine 1f
a
b
Reactions were run using 1f (0.3 mmol), 2 (0.6 mmol), and powdered activated 3 Å molecular sieves (300 mg) in DCM (3 mL) at rt. Product
3fa was obtained in 89% yield and with 83% ee when the reaction was performed on a 1 mmol scale of tryptamine 1f.
trace of difunctionalization. In a similar manner, with 3-
acetylbenzaldehyde 2t, the gold-catalyzed functionalization
proved totally selective for the aldehyde over the ketone
function. Bicyclic aldehydes were next screened, and it was
shown that 2-naphthaldehyde 2u or 6-quinolinecarboxalde-
hyde 2v was well tolerated, leading to 89 and 74% ee,
respectively. Compound 3fw was obtained with a moderate
51% ee from 1-naphthaldehyde. Interestingly, though, its aza-
analoguous 4-quinolinecarboxaldehyde 2x led to 2fx in a
moderate 34% yield but with excellent 80% ee. Finally, the
piperonaldehyde led to 3fy with 73% ee, introducing the 1,3-
benzodioxole scaffold present in numerous indolic drugs such
as tadalafil.23 Finally aliphatic aldehydes were screened,
pointing out the limitation of this methodology to aromatic
aldehydes. Indeed, with 3-phenylpropanal 2z, the correspond-
ing tetrahydro-β-carboline 3fz was obtained in a low 18% yield
and with 50% ee. Other tryptamines bearing either a
substituent on the indole ring or another group on the
nitrogen were next used under the optimized conditions
(Scheme 4). The reaction tolerated a methyl and a methoxy
group at position five of the indole ring using 2s as the
aldehyde, leading to 3hs and 3js with good enantioselectivities.
When the reaction was performed from N-benzyltryptamine
3a, the product 3as was obtained with excellent 86% ee, which
dropped to 65% ee using an allyl group. A p-methoxy
substituent proved very similar to a benzyl group, leading to
3es with 86% ee and in 67% yield.
The mechanism of the Pictet−Spengler reaction is
controversial in regards to the nature of the addition of the
indole ring to the iminium ii (Scheme 5).24 However,
regardless of the exact mechanism for the cyclization, all
known Pictet−Spengler reactions initially undergo the
formation of an iminium ii from a hemiaminal i and an acidic
catalyst, with this step generating water (Scheme 5, eq 1). The
mechanistic issue associated with the Au(I)-catalyzed version
of this reaction stands in (1) the mechanistic pathway for the
formation of the iminium and water from the hemiaminal,
while the reaction is seemingly performed in the absence of
Scheme 4. Additional Scope
protons and the role of the Au(I) complex during this step
(Scheme 5, eq 2) and (2) the nature of the intermediates
(likely involving covalent bonding with the chiral gold complex
to explain such high levels of enantioselectivity). Our
hypothesis is that the coordination of the π-Lewis acid Au(I)
complex to the indole ring from A via C2 modifies the acidity
of the proton at C2, thereby allowing an intramolecular
dehydration from intermediate B to C (Scheme 5, eq 3).25
However, very little is known about the actual auration of
indoles, with most of the examples being extremely
specific.26,27 The catalytic cycle would then consist of the
formation of the key iminium C from the tryptamine 1,
aldehyde 2, and the gold catalyst through intermediate A. The
addition of the indole ring to the iminium would occur via the
direct addition of C2 to lead to D (or, alternatively, the C3
addition). After a deauration step regenerating the catalytic
species, the product would be obtained (Scheme 6).
The Au(I)-catalyzed Pictet−Spengler reaction of tryptamine
1f with benzaldehyde using AuPPh3 as a model catalyst was
studied by means of density functional theory (DFT)
computations. (See the Supporting Information for details
+
C
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Letter
from the hemiaminal B. Here we focus on the process of
dehydration and the formation of the final product. Figure 1
shows the results obtained on the computed mechanism that
was postulated in Scheme 6. All energies are Gibbs free
energies at 298 K including a solvent correction for
dichloromethane. The hemiaminal complex B, located at
−0.7 kcal/mol, displays the Au(I) fragment at the C2 position
of the indole moiety. The dehydration process involving the
C2−H bond to form iminium C requires 22.7 kcal/mol of free
energy of activation, that is, 22.0 kcal/mol from the reference
system. Subsequently, intermediate C may form the spiro
complex E via C3 attack to the iminium. This virtually
thermoneutral spiroindolization requires only 3.3 kcal/mol of
free energy of activation. It is thus easily reversible.
Importantly, a C3 to C2 C−C bond migration that would
form a six-member ring D could not be modeled, which is
consistent with previous observations in the field of organo-
catalyzed Pictet−Spengler reactions.24 Alternatively, intermedi-
ate C can also be directly cyclized from the C2 position to give
D at the expense of a moderate energy barrier of 4.8 kcal/mol.
This step is appreciably exergonic by 16.6 kcal/mol. Finally,
intermediate D releases the catalyst and the observed product,
lying at −5.7 kcal/mol on the free-energy surface.
Scheme 5. Putative and Proposed Mechanistic Steps for the
Formation of the Key Iminium
Scheme 6. Mechanistic Proposal
In conclusion, we have developed a new route to chiral
tetrahydro-β-carbolines with high enantioselectivities using
Au(I) catalysis. Although limited to aromatic aldehydes, the
reaction tolerates a large number of reactive functions with
high chemoselectivity. The Au(I) complex serves as an
activator by binding to the indole ring, thereby allowing the
formation of the key iminium with concomitant metalation at
C2 of the indole ring. We expect that this new reactivity will
pave the way to new strategies in the growing field of gold
catalysis applied to heterocyclic chemistry.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03656.
and additional computations.) The investigations started by
the computational analysis of the initial steps of the reaction
Figure 1. Computed dehydration pathway and final steps to the product.
D
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Details of the experimental procedures, nuclear magnetic
Letter
Containing an (S)-Imine Reductase. ChemCatChem 2013, 5, 3505−
3508.
resonance spectra, HPLC, and spectroscopical and
computational data (PDF)
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Accession Codes
CCDC 1915147−1915149 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xavier.guinchard@cnrs.fr.
*E-mail: vincent.gandon@u-psud.fr.
ORCID
Vincent Gandon: 0000-0003-1108-9410
Xavier Guinchard: 0000-0003-2353-8236
Notes
(11) (a) Seayad, J.; Seayad, A. M.; List, B. Catalytic asymmetric
Pictet-Spengler reaction. J. Am. Chem. Soc. 2006, 128, 1086−1087.
(b) Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van
Maarseveen, J. H.; Hiemstra, H. Catalytic asymmetric Pictet-Spengler
reactions via sulfenyliminium ions. Angew. Chem., Int. Ed. 2007, 46,
7485−7487. (c) Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de
Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. Enantioselective
BINOL-phosphoric acid catalyzed Pictet-Spengler reactions of N-
benzyltryptamine. J. Org. Chem. 2008, 73, 6405−6408. (d) Huang, D.;
Xu, F.; Lin, X.; Wang, Y. Highly Enantioselective Pictet−Spengler
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N.G.-O. thanks the MESRI and the CHARMMMAT
Laboratory of Excellence (ANR-11-LABX0039) for financial
support. X.G. thanks Dr. Angela Marinetti (ICSN) for her
support. S.Y. thanks the CSC for the Ph.D. grant.
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F
DOI: 10.1021/acs.orglett.9b03656
Org. Lett. XXXX, XXX, XXX−XXX