Gold-Catalyzed Spirocyclization Reactions of N-Propargyl Tryptamines and Tryptophans in Aqueous Media

Article abstract of DOI:10.1021/acs.orglett.0c01370

N-Propargyl tryptamine and tryptophan derivatives that are readily available from both synthetic and biocatalytic approaches undergo gold-catalyzed dearomative cyclizations in aqueous media to the corresponding spirocyclic derivatives. In addition to the efficiency of the method, operating in aqueous media affords a selective entry to C2-unsubstituted spiroindolenines that have long remained unattainable by Au(I) catalysis. Moderate to excellent yields of the desired spirocyclic products bearing various substituents were obtained.

Full text of DOI:10.1021/acs.orglett.0c01370

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Letter
Gold-Catalyzed Spirocyclization Reactions of N‑Propargyl
Tryptamines and Tryptophans in Aqueous Media
Nazarii Sabat, Feryel Soualmia, Pascal Retailleau, Alhosna Benjdia, Olivier Berteau,
and Xavier Guinchard*
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ABSTRACT: N-Propargyl tryptamine and tryptophan derivatives
that are readily available from both synthetic and biocatalytic
approaches undergo gold-catalyzed dearomative cyclizations in
aqueous media to the corresponding spirocyclic derivatives. In
addition to the efficiency of the method, operating in aqueous
media affords a selective entry to C2-unsubstituted spiroindole-
nines that have long remained unattainable by Au(I) catalysis.
Moderate to excellent yields of the desired spirocyclic products
bearing various substituents were obtained.
1
2,3
he Au(I)-catalyzed spirocyclization of indoles tethered
to alkynes is an important reaction, because it leads to
situ reduce the iminium intermediate leading to compounds D
1
0e
T
(Scheme 1, eq 2).
These accomplishments constitute
4
−6
high-value spiroindole alkaloids.
However, the mechanisms
indirect evidence for the intermediacy of the spirocyclic
vinylgold species ii. However, still the actual C2-unsubstituted
spiroindolenines remain inaccessible, at least with classical
electron-withdrawing protecting groups on the nitrogen.
The development of catalytic reactions in aqueous media is a
rapidly growing field, not only because of environmental
concerns but also because of the unique selectivities that water
associated with this reactivity are somewhat labyrinthic.
Activation of the triple bond by the cationic Au(I) complex
initiates the kinetically favored formation of spirocyclic
vinylgold intermediate ii. However, this key intermediate
then evolves differently, depending on the C2-substitution of
the indole ring (Scheme 1, eq 1).
13
(
1) C2-substituted compounds undergo protodeauration to
the chiral spiroindoles iii (Path A).
2) Unsubstituted compounds (Path B) lead to the
annulated product iv, supposedly as the result of a C3-
to-C2 migration from ii.
3) A nucleophile can trap the spirocyclic vinylgold
intermediate and lead to the reduced spirocyclic
properties may bring to a given reaction. Considering the
robustness of gold catalysts when exposed to moisture and
oxygen, water has been used successfully as a (co)solvent in
7
(
14
gold catalysis.
7a,8,9
We hypothesized that operating in a polar, protic media
would fasten the protodeauration step and potentially allow the
isolation of the spiroindolenines, even with unsubstituted
compounds. In this paper, we report the gold-catalyzed
spirocyclizations of tryptamine and tryptophan derivatives 1
in aqueous media, delivering a range of spiroindolenines 2
(
(
10
compounds v (Path C).
4) If the protodeauration of the spiro intermediate ii is
slow, because of the potential reversibility of the
spirocyclization step, then a direct C2 addition (Path
D) leading to the thermodynamic product iv is not to be
(
Scheme 1, eq 3). In particular, we show that the use of water
media allows the selective formation and isolation of the C2-
unsubstituted spiroindolenines.
We first sought suitable conditions to promote the
spirocyclization of a model 2-methyl-N-nosyl-N-propargyl
1
1
precluded.
In the tryptamine series, Echavarren showed, for instance, that
N-propargyl tryptamines A bearing electron-withdrawing
groups (R = EWG) lead exclusively to the hexahydroazepino-
7a
Received: April 20, 2020
[
4,5-b]indole B (Scheme 1, eq 2), while we reported that
spiroindolenines C can be selectively obtained only if electron-
donating groups are involved (R = EDG) (Scheme 1, eq
11b,12
2
).
Recently, You and Zhang triggered cyclizations in the
presence of a Hantzsch ester acting as an hydride donor to in
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01370
A
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Scheme 1. Selectivities in Gold-Catalyzed Cyclizations of
Alkyne-Tethered Indole Derivatives
1). We then identified that mixtures of MeCN and water yields
high conversions of spiroindolenine 2a (Table 1, entry 2;
higher amounts of water lead to reduced conversions, see the
Supporting Information for the full optimization table). Next,
we turned our attention to the more-challenging cyclization of
C2-unsubstituted tryptamine 1b upon gold-catalyzed con-
ditions in aqueous phase and analyzed the crude mixtures by
1
H nuclear magnetic resonance (NMR). This reaction can
deliver three distinct products, namely, the desired spiroindo-
lenine 2b, the hexahydroazepino[4,5-b]indole 4b and the
tetrahydro-1H-azocino[5,4-b]indole 5b (potentially resulting
from the direct 8-endo addition of the indole), that are easily
separable on silica gel. We first verified that the reaction
performed in organic solvent leads in all cases to the exclusive
high yielding formation of the formal 7-exo addition product
7a
4
b, as reported by Echavarren (Table 1, entry 3). When the
reaction was performed in micellar conditions at 60 °C, despite
partial conversion, the main product appeared to be the
16
spiroindolenine 2b (Table 1, entry 4). We next attempted
catalyst 3a in a 4:1 mixture of H O/MeCN, leading to 4b
2
equimolar to 2b (Table 1, entry 5). With the idea that the
addition of an acid would even better facilitate the
17
protodeauration, we introduced a small proportion of acetic
acid to the solvent system that led as expected to a higher
amount of desired spirocycle 2b (Table 1, entry 6). We then
found that catalyst 3b delivered the same 49% yield of 2b, but
resulted in the increase of 8-membered ring product 5b at the
expense of 4b (Table 1, entry 7). This is remarkable since
product 5b was known so far to result from cyclizations using
only AuCl or AuCl catalysts, but not from catalysts bearing a
tryptamine 1a in an aqueous environment to ensure the
possibility to make this chemistry under aqueous conditions
3
7a
phosphine ligand. The proportion of 2b increased with
higher amount of acetic acid (Table 1, entry 8) and the switch
of the organic cosolvent to dimethylsulfoxide (DMSO) led to
61% of desired spiroindolenine 2b (Table 1, entry 9). A
decrease of the reaction time to 4 h and the catalyst loading to
(
Table 1, entries 1 and 2). Screening of micellar conditions
using TPGS-750 M (D,L-α-Tocopherol methoxypolyethylene
glycol succinate) as the surfactant and the Echavarren
15
catalyst 3a resulted in moderate conversions (Table 1, entry
Table 1. Optimization of the Gold-Catalyzed Cyclizations in Aqueous Media
NMR Yield (%)
1b 2b
a
entry
1
2
R
catalyst (mol %)
solvents
TPGS-750-M
1a
2a
4b
5b
Me
Me
3a (10)
3a (7)
37
−
63
b
H O/MeCN (2:1)
2
100 (92)
c
c
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
3a (10)
3a (10)
3a (10)
3a (10)
3b (10)
3b (10)
3b (10)
3b (7)
MeCN or PhMe or DCE
TPGS-750-M
−
15
7
8
7
3
7
5
10
−
96
32
4
7
7
8
46
43
49
49
55
61
H O/MeCN (4:1)
2
43
H O/MeCN/AcOH (8:2:1)
2
35
17
19
7
H O/MeCN/AcOH (8:2:1)
2
27
23
25
25 (19)
13 (6)
H O/MeCN/AcOH (8:1:2)
2
H O/DMSO/AcOH (8:1:2)
2
b
,
d
1
1
0
1
H O/DMSO/AcOH (8:1:2)
2
60 (48)
62 (51)
10 (4)
14 (7)
b
,d
3a (7)
H O/DMSO/AcOH (8:1:2)
2
a
b
c
The NMR yield was determined using 1,3,5-trimethoxybenzene as an internal standard. Yields in parentheses are isolated yields. Yield given for
d
the reaction performed in MeCN. Reaction time = 4 h. TPGS-750-M = D,L-α-tocopherol methoxypolyethylene glycol succinate.
B
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Scheme 2. Scope of the Gold-Catalyzed Spirocyclizations of Tryptamine and Tryptophan Derivatives
7
5
mol % allowed to isolate the spiroindolenine 2b in average
0% yields and high selectivities, using either catalyst 3a or 3b
(Table 1, entries 10 and 11).
7
c,20
It is clear from these results that water offers interesting
opportunities in this complex mechanistic scenario and that
concomitant efforts directed at the identification of the gold
complex and the solvent system can reverse selectivities
thiophenyl moiety was introduced at C2 and led to the
product 2g in 64% yield. We next switched to tryptophan
21
derivatives as starting materials and could isolate spiroox-
18
obtained toward one or the other compounds of the series.
indole 2h and spiroindolenines 2i and 2j in excellent yields and
2
2
Interestingly, we also never observed any product resulting
from the potential gold-catalyzed hydration of the triple bond
diastereoselectivities. We next exposed racemic 2-Me
tryptophan derivatives 1k−1m to cyclization conditions and
obtained the corresponding spiroindolenines rac-2k, rac-2l,
and rac-2m in excellent yields and diastereoselectivities.
Notably, the reaction worked well with unprotected amine
1l. Next, we engaged a series of challenging C2-unsubstituted
tryptamines/tryptophans 1b and 1n−1t under the established
conditions. Product 2b was obtained in 51% isolated yield
(that value decreased to 45% on a 1.0 mmol scale).
Gratifyingly, compound 2b crystallized and led to the
19
under those conditions.
A series of C2-substituted tryptamines 1a−1g were then
engaged in gold-catalyzed cyclizations, using 7 mol % of 3a to
ensure full conversions within a few hours. (See Scheme 2.)
The reference spiroindolenine 2a was obtained in 91% yield on
a 1.0 mmol scale. The introduction of chlorine and methoxy
substituents at the 5-position of the indole had no impact on
the reaction, delivering 2c and 2d in excellent yields. With a
C
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corresponding X-ray structure. Remarkably, one of our
crystallization attempts led to the formation of the crystalline
trimer 6 (see Figure 1, H have been omitted for clarity
Scheme 3. Biocatalyzed Access to Enantioenriched
Tryptophane Derivatives 9 and Their In Situ
Functionalizations/Spirocyclizations
Figure 1. X-ray structure of trimer 6.
purpose). Despite the fact that this equilibrated trimerization
Finally, we studied the deprotection of the nosyl group of
spiroindolenines to afford secondary amines that would be
ready for further functionalization. Standard conditions using
thiophenol and potassium carbonate on spiroindolenine 2a led
to the isolation of the spiropiperidine 10 in 89% yield (see
Scheme 4). We wanted these conditions to be applicable in the
23
has been known from the 1930s, crystal structures of
spiroindolenines in a trimeric form have not been reported so
far. From our experimental observations, we eventually
concluded that compound 2b undergoes partial trimerization
when it goes from solution to solid state, which is why the
NMR spectrum of the purified compound does not show
absolute purity and isolated yields are typically lower than
NMR yields. We could show that the pure compound is easily
obtained from purification on silica gel by concentration of the
organic phase in the presence of a nonvolatile deuterated
Scheme 4. Deprotection of the Nosyl Group: A One-Pot
Cyclization/Deprotection Strategy To Access Unprotected
Spiroindolenine
solvent (i.e., d -DMSO) to prevent solidification.
6
We next engaged 5-methoxytryptamines, 5-chlorotrypt-
amines, and 5-methyltryptamines 1n−1p in the cyclizations
and obtained the spiroindolenines in similar average of 53%
yields. The replacement of the nosyl group by a tosyl decreased
the yield of 2q to 43%. The use of a tryptophan-derived
starting material led to the spiro compound 2r in 47% yield.
We next used N-propargyl tryptamines 1s and 1t to obtain the
two spiroindolenines 2s and 2t in excellent yields and
chemoselectivities. Those tryptamines with their electron-
donating groups show a similar level of regioselectivity when
11b
operating in an organic solvent.
Some of the tryptophan spirocyclic compounds (2k−2m)
were racemic, because of synthetic reasons. We sought an
alternative approach allowing access to enantiopure products.
We turned to biocatalysis since it is a powerful and unique
24
approach in the toolbox of organic chemists. Tryptophan
2
5
synthase allows, in theory, simple access to a variety of
enantiopure tryptophan derivatives from inexpensive serine
aqueous phase, and, for this purpose, we developed a one-pot
procedure combining the gold-catalyzed cyclization followed
by the deprotection of the nosyl group via the addition of
thiophenol and potassium carbonate. With this approach, we
obtained the amine 10 in 75% yield, starting from the
tryptamine 1a.
In summary, we have developed an efficient strategy to
access spiroindolenines using gold catalysis under aqueous
conditions with high yields, starting from tryptamine and
tryptophan derivatives. Beyond the fact that operating with
water as the main solvent partially answers questions regarding
the general transitioning that organic synthesis must do toward
greener approaches, we showed here that water also has much
to offer, in terms of chemoselectivity and regioselectivity. We
were able, in particular, with these conditions access hitherto
unattainable electron-poor spiroindolenines with high regiose-
lectivities. The combination of biocatalysis and synthetic
methods leading to enantiopure compounds in high efficiency
26
and indole derivatives. After the expression and purification
of the required enzyme, we applied this strategy to a series of
2
-methylindole derivatives 8 (R = H, OMe, F) and easily
obtained the corresponding tryptophan analogues 9 (see
Scheme 3). The enzymatic crude mixtures were subjected to
protein precipitation, then filtered and lyophilized. Propargy-
lation was then performed directly on the crude products,
leading to fully propargylated intermediates. The gold-
catalyzed cyclization in aqueous conditions then afforded the
spiro derivatives 2u−2w in excellent global yields and
diastereoselectivities over three steps. This strategy, implying
just a final purification, proved to be very efficient to access
densely functionalized enantiopure spiroindolenines. The
enantiomeric excess measured on 2u by chiral high-perform-
ance liquid chromatography (HPLC) (>99.5%) showed that
the entire sequence is totally stereoretentive.
D
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also demonstrates that the introduction of biocatalysis to
synthetic schemes is more relevant than ever.
(3) For reviews on indole spirocyclizations, see: (a) Roche, S. P.;
Youte Tendoung, J.-J.; Treg
591. (b) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P.
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3
Chem. - Eur. J. 2016, 22, 2856−2881. (c) Bariwal, J.; Voskressensky,
ASSOCIATED CONTENT
sı Supporting Information
■
L. G.; Van der Eycken, E. V. Chem. Soc. Rev. 2018, 47, 3831−3848.
*
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(
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01370.
5) For reviews on gold catalysis involving alkynes, see: (a) Bandini,
M. Chem. Soc. Rev. 2011, 40, 1358−1367. (b) Ohno, H. Isr. J. Chem.
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Details of the experimental procedures, nuclear magnetic
resonance (NMR) spectra, HPLC, spectroscopical data
(PDF)
(6) For selected recent examples using various catalysts, see:
(
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Accession Codes
(
CCDC 1975694−1975699 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.
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AUTHOR INFORMATION
Corresponding Author
́
■
́
Xavier Guinchard − Universite Paris-Saclay, CNRS, Institut de
́
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette,
France; orcid.org/0000-0003-2353-8236;
Email: xavier.guinchard@cnrs.fr
Marinetti, A.; Voituriez, A.; Guinchard, X. Molbank 2018, M985.
(e) Glinsky-Olivier, N.; Retailleau, P.; Guinchard, X. Eur. J. Org.
Chem. 2018, 2018, 5823. (f) Xu, W.; Wang, W.; Wang, X. Angew.
Chem., Int. Ed. 2015, 54, 9546−9549. (g) Zhang, L.; Wang, Y.; Yao,
Z.-J.; Wang, S.; Yu, Z.-X. J. J. Am. Chem. Soc. 2015, 137, 13290−
13300.
Authors
Nazarii Sabat − Universite
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette, France
Paris-Saclay, INRAE,
(
8) (a) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351,
517−1522. (b) Hashmi, A. S. K.; Yang, W.; Rominger, F. Adv. Synth.
Catal. 2012, 354, 1273−1279.
9) In a more general context, intramolecular cyclizations of indoles
́
Paris-Saclay, CNRS, Institut de
1
Feryel Soualmia − Universite
́
(
AgroParisTech, Micalis Institute, ChemSyBio, 78350 Jouy-en-
Josas, France
on electrophiles delivering 2-substituted products are often argued to
evolve via spiroindolenines by C3 to C2 migrations. See, for example:
Pascal Retailleau − Universite
Chimie des Substances Naturelles, 91198 Gif-sur-Yvette, France
Paris-Saclay, INRAE,
́
Paris-Saclay, CNRS, Institut de
(a) Zhuo, C.-X.; Wu, Q.-F.; Zhao, Q.; Xu, Q.-L.; You, S.-L. J. Am.
Chem. Soc. 2013, 135, 8169−8172. (b) Loh, C. C. J.; Raabe, G.;
Alhosna Benjdia − Universite
́
Enders, D. Chem. - Eur. J. 2012, 18, 13250−13254.
AgroParisTech, Micalis Institute, ChemSyBio, 78350 Jouy-en-
Josas, France
(10) For selected recent examples, see: (a) Cera, G.; Chiarucci, M.;
Mazzanti, A.; Mancinelli, M.; Bandini, M. Org. Lett. 2012, 14, 1350−
1353. (b) Modha, S. G.; Kumar, A.; Vachhani, D. D.; Jacobs, J.;
Olivier Berteau − Universite Paris-Saclay, INRAE,
́
AgroParisTech, Micalis Institute, ChemSyBio, 78350 Jouy-en-
Josas, France; orcid.org/0000-0002-3434-5168
Sharma, S. K.; Parmar, V. S.; Van Meervelt, L.; Van der Eycken, E. V.
Angew. Chem., Int. Ed. 2012, 51, 9572−9575. (c) Kumar, A.;
Vachhani, D. D.; Modha, S. G.; Sharma, S. K.; Parmar, V. S.; Van der
Eycken, E. V. Beilstein J. Org. Chem. 2013, 9, 2097−2102. (d) Podoll,
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01370
Notes
(
11) (a) Liddon, J. T. R.; Rossi-Ashton, J. A.; Clarke, A. K.; Lynam,
J. M.; Taylor, R. J. K.; Unsworth, W. P. Synthesis 2018, 50, 4829−
836. (b) Magne, V.; Marinetti, A.; Gandon, V.; Voituriez, A.;
Guinchard, X. Adv. Synth. Catal. 2017, 359, 4036−4042.
12) Interestingly, Van der Eycken reported that tryptamines 2-
The authors declare no competing financial interest.
4
́
ACKNOWLEDGMENTS
■
(
(
N.S. thanks the CHARMMMAT Laboratory of Excellence
No. ANR-11-LABX0039) for financial support. This work was
supported by European Research Council Consolidator Grant
No. 617053 to O.B.
propynoic amides lead to mixtures of compounds B and C in
moderate yields. See ref 10c.
(
13) (a) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A.
Angew. Chem., Int. Ed. 2007, 46, 3798−3800. (b) Grela, K.; Gułajski,
Ł.; Skowerski, K. Alkene Metathesis in Water. In Metal-Catalyzed
Reactions in Water; Dixneuf, P. H., Cadierno, V., Eds.; Wiley−VCH:
Weinheim, Germany, 2013; Chapter 8, pp 291−336. (c) Kitanosono,
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Letter
(
16) In addition, we reacted 2b with TFA or catalyst 3a. In both
cases, 2b remained unchanged, ensuring that compound 4b is not the
result of a 1,2-shift from spiroindolenine 2b, as it is well-known in the
Pictet−Spengler reactions. For recent papers, see: (a) Zheng, C.; Xia,
Z.-L.; You, S.-L. Chem. 2018, 4, 1952−1966. (b) Gobe, V.; Gandon,
́
V.; Guinchard, X. Adv. Synth. Catal. 2018, 360, 1280−1288.
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18) As a side observation, we also noted that the reaction
(
(
(
performed with Me SAuCl in MeCN affords exclusively the 8-
2
membered ring product 5b, while operation in a H O:MeCN mixture
2
(
2:1) leads mainly to the 7-membered ring 4b (4b:5b ratio: 2/1). In
both cases, no trace of the spiro compound 2b was observed. See the
Supporting Information.
(
19) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem.,
Int. Ed. 2002, 41, 4563−4565.
20) For other papers reporting similar strategies, see: (a) Miyake, F.
Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2004, 6, 711−713.
b) Liddon, J. T. R.; Clarke, A. K.; Taylor, R. J. K.; Unsworth, W. P.
Org. Lett. 2016, 18, 6328−6331.
21) See the Supporting Information for all details regarding the
synthesis of the tryptophan starting materials.
22) The relative and absolute stereochemistries of the main
(
(
(
(
diastereoisomers were easily determined to be S,S from NOESY
experiments, showing an interaction between H4 of the indole ring
and the H adjacent to the ester group. See the Supporting
Information.
(
23) (a) Robinson, R.; Suginome, H. J. Chem. Soc. 1932, 298−304.
b) Hoshino, T. Justus Liebigs Ann. Chem. 1933, 500, 35−42.
24) (a) Hailes, H. C.; Dalby, P. A.; Woodley, J. M. J. J. Chem.
(
(
Technol. Biotechnol. 2007, 82, 1063−1066. (b) Sheldon, R. A.;
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(
25) Caulkins, B. G.; Young, R. P.; Kudla, R. A.; Yang, C.; Bittbauer,
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Mueller, L. J. J. J. Am. Chem. Soc. 2016, 138, 15214−15226.
(
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4
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F
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