Enantioselective synthesis of spiroimines by asymmetric decarboxylative alkylation/isomerization/[3+2]-cycloaddition reaction of azidoalkenes

Article abstract of DOI:10.1002/ejoc.201403161

The synthesis of chiral spiroimines, one of the pharmacophores of the marine neurotoxin gymnodimine A is described. The approach relies on a three-step sequence that includes a palladium-catalyzed asymmetric decarboxylative alkylation, an isomerization and a [3+2]-cycloaddition reaction of an azidoalkene to build the imine.

Full text of DOI:10.1002/ejoc.201403161

FULL PAPER
DOI: 10.1002/ejoc.201403161
Enantioselective Synthesis of Spiroimines by Asymmetric Decarboxylative
Alkylation/Isomerization/[3+2]-Cycloaddition Reaction of Azidoalkenes
Matt Rambla,[a] Leslie Duroure,[a] Laurent Chabaud,*[a] and Catherine Guillou*[a]
Keywords: Asymmetric synthesis / Azides / Cycloaddition / Palladium / Spiro compounds
The synthesis of chiral spiroimines, one of the pharmaco-
phores of the marine neurotoxin gymnodimine A is de-
scribed. The approach relies on a three-step sequence that
includes a palladium-catalyzed asymmetric decarboxylative
alkylation, an isomerization and a [3+2]-cycloaddition reac-
tion of an azidoalkene to build the imine.
the spirocyclic imine is one of the pharmacophores of the
natural product.[6] Herein, we report a straightforward
enantioselective synthesis of analogs of the spiroimine core
of GYM A (1), which includes a Pd-catalyzed asymmetric
decarboxylative alkylation reaction, an isomerization step
and a [3+2]-cycloaddition reaction of an azidoalkene.
The Pd-catalyzed asymmetric decarboxylative alkylation
reaction of N-heterocycle-containing β-keto esters has re-
cently emerged as a useful method for the enantioselective
synthesis of carbazolones,[7,8] indolones,[7a] lactams,[9] and
imido esters.[10] The decarboxylation of substrates that bear
a nitrogen atom on the pendant alkyl side chain has been
exemplified with a nitrile group,[7,8,11] pyridine,[11b] ind-
ole[11b] or protected primary amine.[11a] Recently, one exam-
ple of asymmetric decarboxylation was reported with a β-
keto ester that contained an azido group on the alkyl
chain.[7] To devise a short and convergent synthesis of spi-
roimines, we envisioned to set the stereochemistry of the
quaternary carbon atom by a Pd-catalyzed decarboxylation
of azido β-keto ester (Ϯ)-2 (Scheme 1). Isomerization of the
allyl moiety of 3 followed by an azidoalkene [3+2]-cyclo-
Introduction
The marine toxin (–)-gymnodimine A (GYM A, 1; Fig-
ure 1) was first isolated in 1995 by Yasumoto et al. from
oysters collected off the coast of New Zealand.[1] The rela-
tive and absolute configurations were later elucidated by
Munro and Blunt through X-ray crystallographic studies of
an N-acylated derivative of gymnodamine, the reduced im-
ine form of GYM A.[2]
Figure 1. Structure of the neurotoxin (–)-gymnodimine A (1).
GYM A (1) is produced by the dinoflagellate Karenia sel-
liformis (Gymnodinium selliforme) and belongs to the family
of spiroimine. GYM A (1) was found to give positive re-
sponses in the mouse bioassay for neurotoxic shellfish poi-
soning with an LD50 of 80 μg/kg by intraperitoneal injec-
tion[3] and 755 μg/kg by oral administration.[4] Later, Molgó
and co-workers showed that 1 blocks muscular and neu-
ronal nicotinic acetylcholine receptors (nAChRs).[5] Co-
crystallization of GYM A (1) with the acetylcholine binding
protein (AChBP) pointed out the key role of the protonated
imine in the binding with AChBP.[5] We also recently
showed that 6,6-spiroimine analogs of 1 displayed antago-
nist activity on nAChRs, which supports the hypothesis that
[a] Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, CNRS, LabEx LERMIT,
1 avenue de la Terrasse, 91198 Gif-sur-Yvette, France
E-mail: laurent.chabaud@cnrs.fr
catherine.guillou@cnrs.fr
http://www.icsn.cnrs-gif.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403161.
Scheme 1. Approach to spiroimines 5.
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 7716–7720
7716

Enantioselective Synthesis of Spiroimines from of Azidoalkenes
addition reaction of 4 should furnish optically active Table 2. Decarboxylation reaction of azido β-keto esters (Ϯ)-2.
spiroimines 5.
Results and Discussion
Our studies began with the examination of the optimal
catalytic system for the Pd-catalyzed asymmetric decarb-
oxylative alkylation reaction of azido β-keto ester (Ϯ)-2a
(Table 1). When the reaction was conducted under the con-
ditions developed by Trost and co-workers,[12] by using
either (R,R)-DACH ligand (L1) or (R,R)-ANDEN ligand
(L2) in dioxane, no reaction occurred (Table 1, Entries 1
and 2).
The use of Stoltz’s conditions, namely (S)-tBuPHOX li-
gand (L3) in combination with Pd2(pmdba)3 in toluene,
gave the desired allyl azide 3a in 78% yield and 87% ee
(Table 1, Entry 3). An improved isolated yield (87%) was
obtained when the reaction was performed in diethyl ether
at 35 °C (Table 1, Entry 4). However, changing the ligand
to (R)-iPrPHOX (L4) did not improve the results and fur-
nished the opposite enantiomer in lower ee (Table 1, En-
try 5).
With the optimized conditions in hand, we tested the
series azido β-keto esters (Ϯ)-2b–2k. As shown in Table 2,
the reaction with cyclohexanone (Ϯ)-2b furnished 3b in
74% yield with 88% ee. The reaction performed well with
a longer alkyl side chain, such as an azidobutyl (3c, 74%,
82% ee). Similarly, enantioenriched cyclopentanone 3d and
cycloheptanone 3e were obtained in 68 and 80% yield,
respectively, and both with 87% ee.
Tetralone derivatives 3f and 3g were produced in good
yields in 89 and 90% ee for the propyl and the butyl azides,
[a] Reaction carried out in toluene at 50 °C. [b] Pd2(pmdba)3
(4 mol-%), ligand L3 (10 mol-%) were used.
respectively. Heteroaromatic β-keto ester 2h provided allyl
Table 1. Selected conditions optimization [pmdba = bis(p-methoxybenzylidene)acetone].
Entry
Catalyst
Ligand
Solvent
Yield [%][a]
ee [%][b]
1
2
3
4
5
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(pmdba)3
Pd2(pmdba)3
Pd2(pmdba)3
L1
L2
L3
L3
L4
dioxane
dioxane
toluene
Et2O
n.r.[c]
n.r.[c]
78
87
73
–
–
87
87
–62
Et2O
[a] Isolated yield by flash chromatography. [b] Determined by chiral HPLC. [c] No reaction.
Eur. J. Org. Chem. 2014, 7716–7720
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7717

M. Rambla, L. Duroure, L. Chabaud, C. Guillou
FULL PAPER
azide 3h in 60% yield and 86% ee. The decarboxylative
Isomerized olefins 4 were next subjected to the key step
allylation reaction of vinylogous thioesters 2i and 2j was of the sequence: the azidoalkene [3+2]-cycloaddition reac-
carried out under slightly modified conditions to give azido tion.[13] It is well established that under thermal conditions
ketones 3i and 3j in good yields and enantiomeric excesses. or microwave irradiation[14] the cycloaddition reaction of
Finally, we observed that optimal conditions led to the for- azides with olefins produces 1,2,3-Δ2-triazolines, that are
mation of N-heterocyclic compound 3k with 64% yield and usually unstable and evolve to the formation of imines and/
86% ee.
or aziridines. To test the cycloaddition reaction, we selected
Isomerization of the allyl group to propenyl was per- azidoalkene 4f to form spirocyclic imine 5f (Table 4).
formed in the presence of 10 mol-% of Pd(PhCN)2Cl2 in
toluene at 60 °C under microwave irradiation (Table 3). Un-
Table 4. [3+2]-Cycloaddition reaction of azidoalkene 4f.
der these conditions nearly complete conversion was
achieved, except for compound 3g that was partially con-
verted into 4g (86% conversion). Furthermore, N-hetero-
cyclic ketone 3k was inert toward the reaction conditions.
All other substrates 3a–3f, 3h and 3i furnished 1,2-disub-
stituted olefins 4a–4f, 4h and 4i exclusively as the (E) iso-
mer, as an inseparable mixture with the starting material.
For cyclopentanone 3d, better conversion (96% conversion,
94% isolated yield) was achieved when the reaction was
carried out with Crabtree’s catalyst in CH2Cl2 at 25 °C.
Table 3. Isomerization of allyl azides 3.[a]
Entry Solvent
Temp. Time
Ratio[a]
6f/5f/7f
5f
[%]
7f
[%]
[°C]
[min]
[c]
1
2
3
4
5
MeOH
DMF
THF
toluene
toluene
140
140
160
160
160
210
150
180
60
n.d.[b]
25
16
63
–
–
–
[c]
n.d.[b]
[d]
33:51:16
16:57:27
n.d.[b]
63
21[e]
[c]
60
17[f]
–
[a] Determined by 1H NMR spectroscopy of the crude mixture.
[b] Not determined. [c] Not observed. [d] Not isolated. [e] dr =
82:18. [f] Isolated yield over two steps (isomerization–cycloaddition
reaction).
We found that when a polar protic solvent (MeOH;
Table 4, Entry 1) or aprotic solvent [N,N-dimethylform-
amide (DMF); Table 4, Entry 2] was used, extensive decom-
position was observed, which resulted in a low isolated yield
of spiroimine 5f. Irradiation of 4f in tetrahydrofuran (THF)
for 180 min (Table 4, Entry 3) allowed us to identify tri-
azoline 6f, imine 5f, and aziridine 7f in the crude mixture
(ratio 33:51:16). However, after purification over silica gel,
only spiroimine 5f was isolated in a good 63% yield.
Switching the solvent to toluene (Table 4, Entry 4) led to a
shorter reaction time. Under these conditions, spirocyclic
imine 5f was isolated in 63% yield and aziridine 7f in 21%
yield as a 82:18 mixture of diastereomers. The fact that the
isolated yield of 5f was higher than its proportion in the
crude mixture suggests that the acidity of the silica gel pro-
motes decomposition of triazoline 6f into 5f and/or 7f.[15]
Finally, we tested a one-pot procedure that involved Pd-
catalyzed isomerization of 3f in toluene at 60 °C under
microwave irradiation, followed by cycloaddition at 160 °C
for 60 min (Table 4, Entry 5). However, the isolated yield of
spiroimine 5f was lower than the two-step procedure (17
versus 52%) owing to extensive decomposition.
[a] Isolated yield of inseparable alkene 4 and starting material.
[b] Reaction was carried out with Crabtree’s catalyst (3.75 mol-%)
in CH2Cl2 at 25 °C.
The optimal conditions were then applied to the cyclo-
addition reaction of azidoalkene 4a (Table 5). Both imine
7718
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7716–7720

Enantioselective Synthesis of Spiroimines from of Azidoalkenes
5a and stable triazoline 6a were obtained in a 50:50 mixture
with toluene as solvent. However, the use of a more polar
solvent, such as 1,2-dichlorobenzene, improved the forma-
tion of imine 5a, which was isolated in 62% yield; although
still with some triazoline 6a (20%). The cycloaddition reac-
tion of saturated cyclic ketones 4b, 4d, and 4e was evaluated
by using the previous optimal conditions. Cyclohexanone
derivative 5b was isolated in 50% yield. We noted that
spiroimines 5d and 5e were rather unstable on silica gel,
which explains the modest isolated yields. These results con-
trast with the observations made with other spiroimines
that showed remarkable stability in acidic conditions.[6,16]
Cyclic ketone substituted by a furan ring 4h afforded imine
5h in a good yield of 54%, as well as aziridine 7h (22%).
Finally, thioenol ether containing spiroimine 5i was isolated
in 35% yield. Our efforts to obtain 6,7-spiroimines from the
cycloaddition reaction of azidoalkenes 4c, 4g, and 4j re-
sulted in extensive decomposition, presumably because of
the low stability of the cycloadducts or the corresponding
imines.
Experimental Section
General Procedure for the Asymmetric Decarboxylative Allylation:
A
solution of Pd2(pmdba) (2.5 mol-%) and (S)-tBuPHOX
(6.25 mol-%) in freshly distilled and degassed diethyl ether (13 mL/
mmol) was prepared under argon. The reaction mixture was stirred
at room temperature for 30 min. A solution of allylic ester
(1.0 equiv.) in freshly distilled and degassed diethyl ether (7 mL/
mmol) was transferred into the reaction vessel by syringe, and the
reaction mixture was heated at 35 °C overnight. Then the mixture
was cooled to room temperature, and the solvent was evaporated
under vacuum. Purification by flash chromatography (heptane to
heptane/EtOAc) gave the corresponding enantioenriched keto allyl
compound.
General Procedure for the Isomerization: A solution of olefin
(1.0 equiv.) in toluene (2.2 mL/mmol) with Pd(PhCN)2Cl2 (10 mol-
%) was warmed under microwave irradiation at 60 °C for 30 min.
Then the mixture was cooled to room temperature, and the solvent
was evaporated under vacuum. The crude mixture was purified by
flash chromatography (heptane to heptane/EtOAc) to afford the
corresponding isomerized product.
General Procedure for the [3+2]-Cycloaddition Reactions: A solution
of azide (1.0 equiv.) in toluene (25 mL/mmol) was heated under
microwave irradiation at 160 °C for 60 min. Then the mixture was
cooled to room temperature, and the solvent was evaporated under
high vacuum. The crude mixture was purified by flash chromatog-
raphy (CH2Cl2 to CH2Cl2/MeOH) to afford the corresponding title
compound.
Table 5. [3+2]-Cycloaddition reaction of isomerized azidoalkenes
4.
Supporting Information (see footnote on the first page of this arti-
1
cle): Experimental procedures, HPLC chromatograms, and H and
13C NMR spectra.
Acknowledgments
The authors thank the Agence Nationale de la Recherche (ANR)
(grant ANR-11-BS07-006-01), the Centre National de la Recherche
Scientifique (CNRS) and the Institute de Chimie des Substances
Naturelles (ICSN)for financial support. M. R. was supported by a
fellowship from the ANR and L. D. by a fellowship from the ICSN.
We also thank Prof. Yannick Landais and Dr. Valérie Desvergnes
(ISM, University of Bordeaux) for helpful discussions.
[1] T. Seki, M. Satake, L. Mackenzie, H. F. Kaspar, T. Yasumoto,
Tetrahedron Lett. 1995, 36, 7093–7096.
[a] Reaction carried out in 1,2-dichlorobenzene at 120 °C.
[2] M. Stewart, J. W. Blunt, M. H. G. Munro, W. T. Robinson,
D. J. Hannah, Tetrahedron Lett. 1997, 38, 4889–4890.
[3] R. Kharrat, D. Servent, E. Girard, G. Ouanounou, M. Amar,
R. Marrouchi, E. Benoit, J. Molgó, J. Neurochem. 2008, 107,
952–963.
[4] R. Munday, N. R. Towers, L. Mackenzie, V. Beuzenberg, P. T.
Holland, C. O. Miles, Toxicon 2004, 44, 173–178.
Conclusions
We have developed a straightforward method to access
enantioenriched spiroimines. The asymmetric construction [5] Y. Bourne, Z. Radic, R. Aráoz, T. Talley, E. Benoit, D. Servent,
P. Taylor, J. Molgó, P. Marchot, Proc. Natl. Acad. Sci. USA
of the quaternary carbon atom was performed by using
a palladium-catalyzed decarboxylative alkylation reaction.
This reaction is compatible with a variety of cyclic ketones
that bear a propyl or butyl azido group, which extends the
substrate scope of this reaction that was exemplified with
only carbazolone.[7] We also showed that isomerization of
the allyl chain followed by a [3+2]-cycloaddition reaction
of the azidoalkene afforded a variety of chiral substituted
spiroimines.
2010, 107, 6076–6081.
[6] L. Duroure, T. Jousseaume, R. Aráoz, E. Barre, P. Retailleau,
L. Chabaud, J. Molgó, C. Guillou, Org. BioMol. Chem. 2011,
9, 8112–8118.
[7] a) C. J. Gartshore, D. W. Lupton, Angew. Chem. Int. Ed. 2013,
52, 4113–4116; Angew. Chem. 2013, 125, 4207–4210; b) C. J.
Gartshore, D. Lupton, Aust. J. Chem. 2013, 66, 882–890.
[8] a) Z. Li, S. Zhang, S. Wu, X. Shen, L. Zou, F. Wang, X. Li, F.
Peng, H. Zhang, Z. Shao, Angew. Chem. Int. Ed. 2013, 52,
4117–4121; Angew. Chem. 2013, 125, 4211–4215; b) X. Shen,
Eur. J. Org. Chem. 2014, 7716–7720
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7719

M. Rambla, L. Duroure, L. Chabaud, C. Guillou
FULL PAPER
R. Zhao, M. Mo, F. Peng, H. Zhang, Z. Shao, J. Org. Chem.
2014, 79, 2473–2480.
[9] D. C. Behenna, Y. Liu, T. Yurino, J. Kim, D. E. White, S. C.
Virgil, B. M. Stoltz, Nat. Chem. 2012, 4, 130–133.
[10] B. N. Bennett, D. C. Duquette, J. Kim, W. Liu, A. N. Marziale,
D. C. Behenna, S. C. Virgil, B. M. Stoltz, Chem. Eur. J. 2013,
19, 4414–4418.
[11] a) D. C. Behenna, J. T. Mohr, N. H. Sherden, S. C. Marinescu,
A. N. Harned, K. Tani, M. Seto, S. Ma, Z. Novák, M. R.
Krout, R. M. McFadden, J. L. Roizen, J. A. Enquist Jr., D. E.
White, S. R. Levine, K. V. Petrova, A. Iwashita, S. C. Virgil,
B. M. Stoltz, Chem. Eur. J. 2011, 17, 14199–14223; b) A. Y.
Hong, N. B. Bennett, M. R. Krout, T. Jensen, A. M. Harned,
B. M. Stoltz, Tetrahedron 2011, 67, 10234–10248.
[12] B. M. Trost, R. N. Bream, J. Xu, Angew. Chem. Int. Ed. 2006,
45, 3109–3112; Angew. Chem. 2006, 118, 3181–3184.
[13] For selected recent examples, see: a) S. Kim, Y. M. Lee, J. Lee,
T. Lee, Y. Fu, Y. Song, J. Cho, D. Kim, J. Org. Chem. 2007,
72, 4886–4891; b) B. W.-Q. Hui, S. Chiba, Org. Lett. 2009, 11,
729–732; c) N. Patel, C. Chambers, K. Hemming, Synlett 2009,
18, 3043–3047; d) B. Tong, B. Hui, S. Chua, S. Chiba, Synthesis
2011, 21, 3552–3562; e) I. De Miguel, B. Herradón, E. Mann,
Adv. Synth. Catal. 2012, 354, 1731–1736; f) I. De Miguel, M.
Velado, B. Herradón, E. Mann, Eur. J. Org. Chem. 2012, 4347–
4353; g) K. Hayashi, H. Tanimoto, H. Zhang, T. Morimoto, Y.
Nishiyama, K. Kakiuchi, Org. Lett. 2012, 14, 5728–5731; h) I.
De Miguel, M. Velado, B. Herradón, E. Mann, Adv. Synth.
Catal. 2013, 355, 1237–1242; i) T. A. Reekie, M. G. Banwell,
A. C. Willis, J. Org. Chem. 2013, 78, 7100–7111; j) K. Suman,
L. Srinu, S. Thennarasu, Org. Lett. 2014, 16, 3732–3735.
V. Santagada, E. Perissutti, F. Fiorino, B. Vivenzio, G. Cali-
endo, Tetrahedron Lett. 2001, 42, 2397–2400.
a) A. Hassner, A. S. Amarasekara, D. Andisik, J. Org. Chem.
1988, 53, 27–30; b) A. Hassner, K. S. Keshava Murthy, Tetrahe-
dron Lett. 1987, 28, 97–100.
[14]
[15]
[16] Y. Ahn, G. I. Cardenas, J. Yang, D. Romo, Org. Lett. 2001, 3,
751–754.
Received: September 2, 2014
Published Online: October 24, 2014
7720
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7716–7720