Surfactant Micelles Enable Metal-Free Spirocyclization of Keto-Ynamides and Access to Aza-Spiro Scaffolds in Aqueous Media

Article abstract of DOI:10.1002/ejoc.201901441

Micellar solutions of cetyltrimethylammonium bromide (CTAB) surfactant allow the spirocyclization of keto-ynamides in an aqueous medium without recourse to transition-metal catalysis, enabling access in water to naturally occurring aza-spiro compounds with potential in drug discovery. The reaction was monitored by dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM), which determined the morphology and change in size of the micelles before and after incorporation of the substrate and achievement of 5-endo-dig cyclization inside the micelles.

Full text of DOI:10.1002/ejoc.201901441

DOI: 10.1002/ejoc.201901441
Communication
Aqueous Micellar Systems
Surfactant Micelles Enable Metal-Free Spirocyclization of Keto-
Ynamides and Access to Aza-Spiro Scaffolds in Aqueous Media
Frédéric Beltran,[a][‡] Andrea V. Vela-Gonzalez,[b][‡] Tatiana Knaub,[a][‡‡] Marc Schmutz,[b]
Marie Pierre Krafft,*[b] and Laurence Miesch*[a]
Abstract: Micellar solutions of cetyltrimethylammonium brom- action was monitored by dynamic light scattering (DLS) and
ide (CTAB) surfactant allow the spirocyclization of keto-ynam- cryogenic transmission electron microscopy (cryo-TEM), which
ides in an aqueous medium without recourse to transition- determined the morphology and change in size of the micelles
metal catalysis, enabling access in water to naturally occurring before and after incorporation of the substrate and achieve-
aza-spiro compounds with potential in drug discovery. The re- ment of 5-endo-dig cyclization inside the micelles.
Introduction
namic light scattering and electron microscopy, have so far only
been applied to the characterization of the empty micelles.[5]
Depending on its location in the micelle, whether in the hydro-
phobic core or in the polar zone formed by the surfactant polar
heads, the substrate can differently impact the size and shape
of the micelle, and hence, the outcome of the reaction. A large
group of bioactive compounds possesses a spirocyclic system
that is usually part of a more complex ring system.[8,9] We re-
ported recently the spontaneous spirocyclization of keto-sulfon-
amides via ynamides in a one-pot process[10] (Scheme 1, reac-
tion a). Furthermore, quaternary ammonium salts allowed the
spirocyclization of non-activated keto-ynamides[11] (Scheme 1,
reaction b) All these reactions were conducted in classical or-
ganic solvents.
Limiting the use of organic solvents in synthesis is currently an
intensely pursued goal.[1] Performing complex reactions in wa-
ter is, however, limited by the poor solubility of most organic
compounds. Micelle-forming surfactants can enable the solubil-
ization of otherwise insoluble compounds. Metal-catalyzed re-
actions carried out in micellar systems have been extensively
studied.[2] In the recent years, the scope of reactions conducted
in micellar systems has significantly broadened with, for exam-
ple, the aerobic oxidation of aryl alkynes[3] the nucleophilic aro-
matic substitution,[4] the sulfonylation of polyfluoroarenes[5]
and the monofluorination of indoles.[6] The use of micellar sys-
tems in the above-mentioned examples also limits the recourse
to transition metal catalysts. These recent advances have made
micelle-enabled reactions possible at an industrial scale with
good reproducibility and low E factor.[7] In this blooming field
it is however striking that, although the size and shape of the
micelles were identified as key to achieve high levels of conver-
sion, hence the concept of “designer” surfactant,[2b] no informa-
tion appears to be available on the effect of the substrate on
the morphology and size of the micelles during the reaction.
To the best of our knowledge, physical techniques, such as dy-
In the present work, we report the first spirocyclization of a
keto-ynamide in micelles of cetyltrimethylammonium bromide
(CTAB) in the absence of any transition metal catalyst. We
proved directly by dynamic light scattering (DLS) and cryogenic
electron microscopy (cryo-TEM) that the substrate is encapsu-
lated in the micelles after deprotonation, and that spirocycliza-
tion occurs subsequently in the inner core of the micelles
(Scheme 1, reaction c).
Reports on the synthesis of spiro compounds in water are
scarce. The only example we are aware of uses sodium stearate
in a Lewis base surfactant-combined catalysis in a three-compo-
nent one-pot reaction.[12] This synthesis led to spirooxindole
derivatives in aqueous micellar media. However, this method
is limited to the use of isatin, malonitrile and 1,3-dicarbonyl
compounds. Although the quaternary center is present in the
target compound, the pyranic structure of the second spiro ring
thus created cannot allow direct access to natural compounds.
[a] Équipe Synthèse Organique et Phytochimie, Institut de Chimie, CNRS-UdS
UMR 7177
4 rue Blaise Pascal, CS 90032, 67081 Strasbourg, France
E-mail: lmiesch@unistra.fr
https://sophy.chimie.unistra.fr
[b] A. Vela Gonzalez, University of Strasbourg , Institut Charles Sadron (CNRS)
23, rue du Loess, 67034 Strasbourg, France
E-mail: krafft@unistra.fr
http://sams.ics-cnrs.unistra.fr/recherche/auto-assemblages-fluores/
[‡] These authors contributed equally to this work.
[‡‡] TK achieved experiments in both Laboratories, the Équipe de Synthèse
Organique et Phytochimie and the Institut Charles Sadron.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901441.
Herein, we explored the 5-endo-dig cyclization starting from
a keto-ynamide solubilized in an aqueous micellar system, while
monitoring the incorporation of the substrate in the micelles
before the onset of the reaction, and eventually the presence
of the final product in the micelles, using DLS and cryo-TEM.
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Scheme 1. Spirocyclization of keto-ynamides.
Results and Discussion
micelles are seen as black dots as reported earlier[14] (Figure 1a).
DLS analysis of micellar CTAB solutions were performed after
adding a NaCl solution (0.8 mol L–1) in order to screen the elec-
trostatic interactions. Figure 1b shows the variation of the auto-
correlation function, the fast decay of which signals the pres-
ence of small circular micelles, in agreement with earlier re-
ports.[15] The deduced size distribution exhibits a predominant
peak centered at ≈ 3.6 nm (polydispersity index 16 %).
We first prepared micellar solutions of a variety of surfactants,
including anionic ones (i.e. sodium dodecylsulfate, SDS) and
neutral ones (i.e. Tween 40, a polyethoxylated sorbitan esteri-
fied by fatty acids; Pluronic-F68, an amphiphilic block copoly-
mer; and TPGS-750-M, a diester comprising racemic α-tocophe-
rol, MPEG-750, and succinic acid), in the presence of one equiv-
alent of a base (tBuONa). In these conditions no spirocyclization
was observed and the starting material was fully recovered
(Supporting Information, Table S1). Then, having recently used
quaternary ammonium salts to perform spirocyclization in or-
ganic solvents,[11] we investigated the spirocyclization of the
keto-ynamide 1 within the organic core of micelles of cetyltri-
methylammonium bromide (CTAB) dispersed in water, and this
without recourse to a transition metal (Scheme 2). Keto-ynam-
ide 1 was prepared via copper catalyzed N-alkynylation of the
corresponding tosylsulfonamide using Hsung's procedure.[13]
Figure 1. a) cryo-TEM image (the arrows indicate the micelle cores seen as
black dots), and b) DLS profile of the micelles formed in solutions of CTAB
(0.03 mol L–1) in aqueous NaCl (0.8 mol L–1), showing the decay of the auto-
correlation function over time (blue) and the variation of the amplitude vs.
the hydrodynamic radius (black).
Scheme 2. Synthesis of aza-spiro compounds in aqueous micellar solutions.
We then incorporated the keto-ynamide 1 in an aqueous
dispersion of CTAB micelles at 30 °C. The substrate/surfactant
ratio was set to 1:25, meaning that ≈ 6 molecules of 1 are
solubilized in one CTAB micelle, knowing that the typical aggre-
gation number in CTAB micelles is around 137 at 30 °C.[16] The
payload in substrate was chosen relatively low in order to facili-
We found that the 5-endo-dig cyclization of keto-ynamide 1
can be successfully achieved in aqueous micellar solutions of
CTAB using NaOH as the base. Micelle morphology and size
were determined before and after introduction of the substrate,
and after completion of reaction.
Solutions of CTAB alone (0.03 mol L–1) in aqueous NaOH tate its incorporation in the organic core of the micelles. The
(0.03 mol L–1) are transparent and consist of a homogeneous addition of 1 resulted in an opacification of the initially trans-
population of spherical micelles, as evidenced by cryo-TEM, the parent micellar solution, indicating that the substrate is not im-
spherical micelles are highlighted with arrows, the core of the mediately solubilized. This was further supported by cryo-TEM
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experiments that show micron-size crystals coexisting with 4). Changing the base from NaOH to LiOH or KOH did not im-
CTAB micelles (Figure 2a) and by absorbance measurements prove the results (Table 1, entries 5, 6). It is noteworthy that
(Figure 2b). The incorporation of the keto-ynamide in the mi- even if the surfactant Triton B leads to spirocycle 2 in the THF/
celles is complete after 2 h, as monitored by light absorbance H2O mixture (100:1.6),[11] Triton B only leads to the starting ma-
experiments that shows that the medium recovers its transpar- terial along with hydrated ynamide (20 %) when the synthesis
ency. Cryo-TEM (Figure 2c) and DLS (Figure 2d) experiments is performed in water (Table 1, entry 7). A gram scale experi-
show that the CTAB micelles (≈ 8.2 nm in radius, polydispersiv- ment with CTAB/NaOH was performed leading to spirocycle 2
ity index 25 %) are loaded with keto-ynamide.
without erosion of the yield.
Table 1. Reactivity of the keto-ynamide 1 in micellar solutions of cetyltrimeth-
ylammonium surfactants CTAB.[a]
Entry
Surfactant Base
Time
Yield [%][b]
[equiv.]
[equiv.]
2 (E/Z ratio)
3
% conv.
100
1
2
3
4
5
6
7
CTAB
(25)
–
NaOH
(25)
NaOH
(25)
NaOH
(25)
NaOH
(10)
LiOH
(1.3)
KOH
(1.3)
Triton B
48 h
48 h
16 h
16 h
16 h
16 h
48 h
79 (95:5)
–[c]
18
–
0
CTAB
(25)
CTAB
(10)
CTAB
(1.3)
CTAB
(1.3)
–
56 (90:10)
39 (88:12)
38 (88:12)
37 (88:12)
–
13
10
–
71
94
48
57
20[d]
–
–
[a] Reactions were conducted at 30 °C. [b] Yield of isolated compounds. [c]
Starting material is totally recovered. [d] 20 % hydrated ynamide was ob-
tained along with starting material.
Figure 2. a) cryo-TEM image taken immediately after incorporation of the
keto-ynamide in the micellar solution showing non-solubilized crystals of
substrate. b) Absorbance spectra of CTAB micelles in water (black), CTAB mi-
celles loaded with keto-ynamide (blue), CTAB micelles containing the aza-
spiro compound (after 48 h, red). c) Cryo-TEM image, and d) DLS of CTAB
micelles (0.03 mol L–1 in 0.8 mol L–1 NaCl) loaded with the keto-ynamide sub-
strate showing the autocorrelation function decay (blue) and the variation of
amplitude vs. hydrodynamic radius (black) after 4 h.
We characterized the micellar solution directly as mixture at
the end of the reaction in the conditions that lead to 79 % of
spiro ester 2 (Table 1 entry 1). Figure 3a shows a cryo-TEM
image of the reaction mixture after 48 h, when the work-up
was initiated. It shows that this mixture is homogeneous (see
also larger field images in Supporting Information, Figure S2)
and only contains small spherical micelles. No crystals or aggre-
gates were observed, which means that all the aza-spiro com-
pound is located in the micelles. DLS measured at different an-
gles confirms the homogeneity of the reaction mixture and
shows a fast decay of the autocorrelation function with time,
reflecting the presence of small spherical micelles ≈ 3.9 nm in
radius (polydispersity index 10 %).
After 48 h of stirring at 30 °C, the reaction medium is trans-
parent and homogeneous. The work-up of the reaction mixture
led to the spiro ester 2 (as an E/Z mixture) in 79 % yield, along
with E spiro acid 3 (18 %) (Table 1, entry 1). It should be noticed
that an exclusive E configuration of the double bond for the
acid was obtained, likely due to a faster saponification of the E-
isomer favored by intramolecular hydrogen bonding between
the carbonyl group and carboxy function of the enamide. Im-
portantly, no reaction was observed in the absence of CTAB; the
keto-ynamide substrate was totally recovered (Table 1, entry 2),
As the micellar conditions used led to a mixture of three
meaning that the micelles are mandatory for the reaction to compounds, we attempted to convert the E/Z mixture of spiro
occur. Reducing the reaction time from 48 h to 16 h led to ester 2 into E-spiro-acid exclusively. Whereas classical saponifi-
incomplete reaction: 30 % of the starting material was recov- cation conditions in organic solvents (i.e. NaOH/MeOH,
ered (Table 1, entry 3). The ester/acid ratio (4:1) remains con- LiOH·H2O/THF/H2O, KOH/DMSO) did not provide acid 3, saponi-
stant. In this case, the reaction medium was still turbid, suggest- fication conducted within the micellar system at 50 °C led to
ing that the keto-ynamide was not totally incorporated in the the desired E-configured acid 3 in 75 % yield (Scheme 3), thus
micelles, as confirmed by micelle sizing (Supporting Informa- emphasizing the scope of the micellar reaction. To the best of
tion, Figure S1). Likewise, decreasing the concentration of CTAB our knowledge saponification of enamides substituted with an
to 10 equivalents also reduces the conversion (≈ 50 % only), ester function has been reported only once in a specific case
while the ester/acid ratio remains constant (4:1) (Table 1, entry of methyleneisoindolinones.[17]
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Figure 3. a) Cryo-TEM image (the arrows indicate the micelle cores seen as
black dots), and b) DLS of CTAB micelles (0.03 mol L–1 in 0.8 mol L–1 NaCl)
containing the aza-spiro compound after completion of the reaction. In b)
autocorrelation function decay over time (blue) and variation of the ampli-
tude vs. the hydrodynamic radius (black).
Scheme 4. a) Schematic representation of spherical CTAB micelles (light blue:
CTAB polar heads, dark blue: Br ions, green: CTAB aliphatic chains). The nega-
tively charged deprotonated keto-ynamide substrate 1.a interacts electrostat-
ically with the positively charged surface of CTAB micelles, leading to its
incorporation at the interface (b). As the reaction proceeds, keto-ynamide 1.a
is converted into the neutral aza-spiro final compound 2, which is preferen-
tially located among the fatty chains that form the core of the micelles (c).
Scheme 3. Saponification of the spiro-enamide within CTAB micelles.
We propose the following mechanism to explain the cryo-
TEM and DLS data (Scheme 4). Keto-ynamide 1 is deprotonated
outside the micelles (1.a). The surfactant selected, CTAB, con-
sists of an amphiphilic cation and a bromide counterion. The
CTAB micelles have positive surface charges and loosely bound
Br– ions (Scheme 4a).[18] This arrangement promotes interac-
tions with the negatively charged keto-ynamide substrate,
which facilitate its incorporation in the micelles. The electronic
interactions between the polar heads of CTAB in the micelles
and the flexible side chain of the keto-ynamide, likely contrib-
ute to a preferred localization of the substrate in the vicinity of
the polar heads (Scheme 4b), leading to the observed signifi-
cant enlargement of the micelles (from ≈ 3.6 nm to ≈ 8.2 nm
in radius). The confinement of the enolate enables the reaction
to take place, and its orientation, with the negatively charged
tertiary enamide oriented toward the positively charged heads
of the micelles, favors the formation of the E configured enam-
ide. This results in higher E/Z selectivity (95:5) as compared to
that obtained when the reaction is performed in organic sol-
vent (77:23).[11]
Conclusion
To sum up, we found that the spiro-cyclization of keto-ynamide
1 can only occur in water when performed in micelles of CTAB
without recourse to metal catalysis. Aza-spiro esters E/Z (95:5)
and the corresponding spiro-acid (100 % E) were obtained with
good yields. The esters can be converted within the micelles in
the pure E acid with 75 % yield. These compounds possess the
aza-spirocyclic framework found in naturally occurring com-
pounds that have powerful bioactivity, and in several synthetic
drugs. To the best of our knowledge, this is the first time that
such compounds are synthesized in aqueous media using mi-
celles as nanoreactors. Cryo-TEM and DLS proved the encapsu-
lation of the substrate and subsequent spirocyclization in the
CTAB micelles. The changes in micelle size during reaction, pro-
vided insights on the interactions between the substrate and
the micelles as well as on the reaction mechanism.
After protonation at the interface by water molecules, the
aza-spiro 2 is no longer charged and exhibits a more compact
structure due to its more rigid tridimensional conformation. As
a consequence, the compound is preferentially located in the
hydrophobic core of the micelle, thus accounting for the even-
tual decrease of the micelle radius to ≈ 3.9 nm (Scheme 4c).
Moreover, the confinement of the substrate in the micelle and
Experimental Section
Supporting Information (see footnote on the first page of this
article): See the Supporting Information for experimental details.
Acknowledgments
the trapping of the hemiacetal at the interface is also advanta- FB thanks the Ministère de la Recherche et de la Technologie
geous for the saponification of the spiro-compound. The fact (MRT) and AV thanks CONACYT (scholarship #459202) for their
that saponification does not occur in organic solvents thus fur- Ph.D scholarships. The authors are also grateful to the Univer-
ther supports the proposed mechanism.
sity of Strasbourg (travel grant for AV), the CNRS and ANR. The
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[8]
[9]
T. M. Williams, C. S. Burgey, T. J. Tucker, C. A. Stump, I. M. Bell, Carbox-
amide spirolactam CGRP receptor antagonists, 2006, WO2006/
031606A2.
P. Y. Ng, H. Davis, K. W. Bair, D. S. Millan, A. Rudnitskaya, X. Zheng, B.
Han, N. Barczak, D. Jr. Lancia, 3-spiro-7-hydroxamic acid tetralins as HDAC
Inhibitors, 2016, WO2016/168660A1.
F. Beltran, I. Fabre, I. Ciofini, L. Miesch, Org. Lett. 2017, 19, 5042–5045.
F. Beltran, L. Andna, L. Miesch, Org. Chem. Front. 2019, 6, 373–376.
L.-M. Wang, N. Jiao, J. Qiu, J.-J. Yu, J.-Q. Liu, F.-L. Guo, Y. Liu, Tetrahedron
2010, 66, 339–343.
Y. Zhang, R. Hsung, M. Tracey, K. Kurtz, E. Vera, Org. Lett. 2004, 6, 1151–
1154.
Z. Lin, J. J. Cai, L. E. Scriven, H. T. Davis, J. Phys. Chem. 1994, 98, 5984–
5993.
R. Dorshow, J. Briggs, C. A. Bunton, D. F. Nicoll, J. Phys. Chem. 1982, 86,
2388–2395.
S. Anachkov, K. Danov, E. Basheva, P. Kralchevsky, K. Ananthapadmanab-
han, Adv. Colloid Interface Sci. 2012, 183–184, 55–67.
M. C. Reddy, M. Jeganmohan, Org. Lett. 2014, 16, 4866–4869.
B. Lindman, G. Lindblom, H. Wennerstrom, N.-O. Persson, H. Gustavsson,
A. Khan, in Magnetic Resonance in Colloid and Interface Science (Eds.: J. P.
Fraissard, H. A. Resing). NATO Advanced Studies Institutes Series. Reidel
Publ., Dordrecht. 1980, pp. 307–320.
electron microscopy platform of the Institut Charles Sadron
(Dr. M. Schmutz) is acknowledged, and Dr. F. Schosseler for help
in the dynamic light scattering measurements.
Keywords: Ynamides · Spirocyclization · Ammonium
surfactants · Micellar catalysis · Dynamic light scattering
[10]
[11]
[12]
[1] B. H. Lipshutz, S. Ghorai, Green Chem. 2014, 16, 3660–3679.
[2] a) B. H. Lipshutz, S. Ghorai, Aldrichim. Acta 2008, 41, 59–72; b) B. H.
Lipshutz, S. Ghorai, A. R. Abela, R. Moser, T. Nishikata, C. Duplais, A. Kra-
sovskiy, J. Org. Chem. 2011, 76, 4379–4391; c) G. L. Sorella, G. Strukul, A.
Scarso, Green Chem. 2015, 17, 644–683; d) S. Handa, B. Jin, P. P. Bora, Y.
Wang, X. Zhang, F. Gallou, J. Reilly, B. H. Lipshutz, ACS Catal. 2019, 9,
2423–2431; e) M. Bihani, P. P. Bora, M. Nachtegaal, J. B. Jasinski, S. Plum-
mer, F. Gallou, S. Handa, ACS Catal. 2019, 9, 7520–7526.
[3] S. Handa, J. Fennewald, B. H. Lipshutz, Angew. Chem. Int. Ed. 2014, 53,
3432–3435; Angew. Chem. 2014, 126, 3500.
[4] N. Isley, R. Linstadt, S. Kelly, F. Gallou, B. Lipshutz, Org. Lett. 2015, 17,
4734–4737.
[13]
[14]
[15]
[16]
[17]
[18]
[5] J. Smith, T. Ansari, M. Andersson, D. Yadagiri, F. Ibrahim, S. Liang, G.
Hammond, F. Gallou, S. Handa, Green Chem. 2018, 20, 1784–1790.
[6] P. P. Bora, M. Bihani, S. Plummer, F. Gallou, S. Handa, ChemSusChem 2019,
12, 3037–3042.
[7] M. Parmentier, C. M. Gabriel, P. Guo, N. A. Isley, J. Zhou, F. Gallou, Curr.
Opin. Green Sustainable Chem. 2017, 7, 13–17.
Received: September 30, 2019
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Communication
Aqueous Micellar Systems
F. Beltran, A. V. Vela-Gonzalez,
T. Knaub, M. Schmutz,
M. P. Krafft,* L. Miesch* .................... 1–6
Surfactant Micelles Enable Metal-
Free Spirocyclization of Keto-Ynam-
ides and Access to Aza-Spiro Scaf-
folds in Aqueous Media
Naturally occurring aza-spiro scaffolds electron microscopy monitoring re-
are synthesized in aqueous micellar vealed the incorporation of the sub-
solutions of a cationic surfactant with- strate and the presence of the reaction
out metal catalysis. Dynamic light scat- products in the micelles.
tering and cryogenic transmission
DOI: 10.1002/ejoc.201901441
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