Iodospirocyclization of Tryptamine-Derived Isocyanides: Formal Total Synthesis of Aspidofractinine

Article abstract of DOI:10.1002/anie.201809678

The N-iodosuccinimide-mediated spirocyclization of tryptamine-derived isocyanides to generate spiroindolenines is reported. The products contain both an imine and an imidoyl iodide as flexible handles for follow-up chemistry. Nucleophilic addition typical

Full text of DOI:10.1002/anie.201809678

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Accepted Article
Title: Iodospirocyclization of Tryptamine-Derived Isocyanides: Formal
Total Synthesis of Aspidofractinine
Authors: Jordy M. Saya, Thomas R. Roose, Jarryt J. Peek, Bram
Weijers, Thomas J. S. de Waal, Christophe M. L. Vande
Velde, Romano V. A. Orru, and Eelco Ruijter
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809678
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10.1002/anie.201809678
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Iodospirocyclization of Tryptamine-Derived Isocyanides: Formal
Total Synthesis of Aspidofractinine
Jordy M. Saya, Thomas R. Roose, Jarryt J. Peek, Bram Weijers, Thomas J. S. de Waal, Christophe M.
L. Vande Velde, Romano V. A. Orru and Eelco Ruijter*[a]
Dedicated to Prof. Dr. Henk Hiemstra on the occasion of his retirement
Abstract: The N-iodosuccinimide-mediated spirocyclization of
tryptamine-derived isocyanides to generate spiroindolenines is
reported. The products contain both an imine and an imidoyl iodide
as flexible handles for follow-up chemistry. Nucleophilic addition
typically occurs chemoselectively on the imine moiety with complete
diastereoselectivity, providing opportunities for the construction of
complex molecular frameworks. The synthetic potential of the
method was showcased in the formal total synthesis of (±)-
aspidofractinine.
acceptors[6]), nucleophilic addition of the isocyanide generates a
highly electrophilic nitrilium ion intermediate. Subsequent
nucleophilic attack of the indole C3 position triggers the
spirocyclization. In the absence of a C2 substituent, the cascade
process is completed by a second cyclization reaction to form
tetracyclic spiroindolines (6 and 8). Considering the robustness
of this process and the high potential utility of efficient and
selective indole spirocyclizations, we wondered whether other
soft electrophiles could give rise to similar cascade cyclizations.
Given the diverse reactivity of imidoyl halides in general and
imidoyl iodides[7] in particular, we considered electrophilic
halogenation as an efficient entry into spiroindolenines 10 and
11 as flexible synthetic intermediates. There is some
precedence for reactions of isocyanides and electrophilic
halogenating agents,[8] including those involving cyclization to
phenanthridines[9] and oxazoles.[10] We were delighted to see
quantitative formation of spiroindolenine 11a-b within 5 min after
treatment of 5a (R1 = R2 = R3 = H) and 5b (R1 = R2 = H, R3 =
Me) with N-iodosuccinimide (NIS) in CDCl3 as the solvent. This
led us to investigate the generality of this reaction and to explore
the reactivity of the resulting products.
Indole alkaloids constitute a large and diverse class of natural
products.[1] These compounds have attracted tremendous
interest from the synthetic community as a result of their diverse
biological activities as well as their challenging molecular
architectures.[2] In particular spiroindoline alkaloids (Fig. 1) have
garnered much attention, as demonstrated by the high number
of approaches to construct the spirocyclic unit.[3] Besides the
interrupted Fischer indole synthesis and aniline condensation
cyclizations, the most common strategy is the intramolecular
dearomatization of indoles to form spiroindolenines. Noteworthy
within this field is the work by MacMillan et al., who have
developed an organocatalytic dearomative cascade approach
toward a range of indoline alkaloids.[4]
Figure 1. Selected naturally occurring indole alkaloids.
Tryptamine-derived isocyanides
5 have shown great
potential in dearomative spirocyclization reactions (Scheme 1).
By addition of a suitable electrophile (i.e. imines[5] or Michael
[a]
J. M. Saya, T. R. Roose, J. J. Peek, B. Weijers, T. J. S. de Waal,
Prof. Dr. Romano V. A. Orru, Dr. E. Ruijter
Department of Chemistry & Pharmaceutical Sciences
Amsterdam Institute for Molecules, Medicines & Systems
Vrije Universiteit Amsterdam
Scheme 1. Tryptamine-derived isocyanides 5 in dearomative couplings with
electrophiles.
De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
E-mail: e.ruijter@vu.nl
Dr. C. M. L. Vande Velde
Faculty of Applied Engineering
Advanced Reactor Technology
Our preliminary studies started by determining the scope
of the reaction with respect to conditions and halogenating
sources. The reaction of 5a with NBS to give the corresponding
imidoyl bromide proceeded less efficiently, while the use of NCS
failed to produce the imidoyl chloride altogether. When we
[b]
University of Antwerp
Groenenborgerlaan 171, 2020 Antwerpen, Belgium
encountered
stability
issues
upon
concentration
of
Supporting information for this article is given via a link at the end of
the document
spiroindolenine 11a, we continued the optimization with 11b. To
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10.1002/anie.201809678
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our delight, the reaction proceeded quantitatively in most organic
solvents. Even methanol was compatible with this reaction as
the imidoyl iodide was formed in 85% yield, without observation
of the imidate.
We then preliminarily probed the reactivity of the two
potential electrophilic sites of 11a, i.e. the imine and the imidoyl
iodide (Scheme 2). After in situ formation of 11a, treatment with
NH3•BH3 (3 eq.) led to complete reduction of both functionalities
to give the saturated spiro product 12, which is the scaffold
structure of known Sky kinase inhibitors.[11] Reaction of 11a with
allylBpin and acetone afforded 13 and 14, respectively, with
>19:1 dr, indicating that one diastereotopic face of the indolenine
is efficiently shielded by the large iodine atom. Finally, we
envisioned that bisnucleophiles could undergo double addition,
resulting in polycyclic spiroindolines. Indeed, reaction of in situ
formed 11a with benzamidine afforded the poorly soluble
polycyclic product 15 in good yield. Interestingly, the
stereochemistry at the indoline C2 position suggests attack from
the more hindered face. This observation led us to conclude that,
while addition of the amidine to the imine may take place
reversibly, formation of 15 proceeds via substitution at the
imidoyl iodide, followed by aminal formation at the C2 position.
Scheme 3. Evaluation of the reactivity of imidoyl iodide 11b. [a] LiHMDS, THF
(0.15 M), −78 °C, 1 h; then Boc2O, −78 °C, 3 h. [b] NaBH4, MeOH:TFE (4:1,
0.2 M), 0 °C to rt, 1 h. [c] Cs2CO3, BnSH, 0 °C, 30 min. [d] 1 M HCl (aq), THF
(0.1 M), 0 °C. Boc = tert-butyloxycarbonyl, Bn = benzyl.
Isocyanides with different indole C2-substituents (tBu, Ph, Br)
were all rapidly converted within 30 min to give the
corresponding imidoyl iodides 11c-e in very good yield. The
double imidoyl halide 11e was surprisingly stable toward
chromatography. Even the homologous isocyanide 5f readily
reacted to form 11f, albeit in moderate yield. The presence of an
ester functionality in the C2 substituent gave the corresponding
spirocyclic product 11g as the enamine tautomer in excellent
yield. As significant decomposition of the spiroindolenines
derived from isocyanides 5h-j was observed during
chromatography, we decided to reduce them in situ to the more
stable spiroindolines 17h-j.[13] Even N1,C2-disubstituted
isocyanide 5i was selectively converted to spiroindoline 17j,
indicating the compatibility of N1-substituents with our method.
Scheme 2. One-pot iodospirocyclization/post-modification strategies to
evaluate the reactivity of imidoyl iodide 11a. [a] NH3•BH3, MeCN (0.1 M), rt, 2
h. [b] allylBPin, CH2Cl2 (0.2 M), rt, 1 h. [c] (CH3)2CO, KOtBu, THF (0.2 M),
−78 °C to rt. [d] benzamidine, 1,4-dioxane (0.1 M), rt, 16 h.
Since imidoyl iodide 11b was found to be stable upon
isolation, we also performed several experiments with this
substrate (Scheme 3). First, we showed that 11b can be
efficiently converted to the Boc-protected enamine 16 after
deprotonation with LiHMDS. Surprisingly, sodium borohydride
reduction resulted in chemoselective conversion of the ketimine
without reducing the imidoyl iodide, affording 17b as a single
diastereomer in near quantitative yield. The relative
stereochemistry of 17b was confirmed by X-ray crystallographic
analysis. For 11b, chemoselective reaction of the imidoyl iodide
also proved possible,[12] furnishing 18 after reaction with benzyl
mercaptan. However, attempts to hydrolyze the imidoyl iodide
under acidic conditions mainly led to decomposition, and only
trace amounts of lactam 19 were observed.
Having established the optimal conditions of the
iodospirocyclization and preliminary reactivity of the resulting
imidoyl iodides, we set out to determine the isocyanide scope.
Since the reaction proceeded smoothly with 5a and 5b, we
Scheme 4. Scope of the C2 substituted tryptamine isocyanides. [a] Reaction
conditions: isocyanide 5 (1 mmol), NIS (1.05 mmol), CH2Cl2 (0.25 M). [b]
Reaction conditions: isocyanide 5 (1 mmol), NIS (1.05 mmol), CH2Cl2 (0.25
M); then NaBH4 (5.0 mmol) in MeOH:TFE (4:1, 0.1 M). [c] Both
iodospirocyclization and reduction steps performed at 0 °C. [d] performed at
1.8 mmol scale.
performed the iodospirocyclization with
a wide variety of
substituted isocyanides 5. As we noted the importance of a C2
substituent on the indole for the stability of the resulting
spiroindolenine, we first subjected C2-substituted isocyanides to
the iodospirocyclization (Scheme 4).
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Next, we shifted our attention to C2-unsubstituted
isocyanides, starting with N1-substituted isocyanides 5k-o
(Scheme 5).[14] In this case, iodospirocyclization would lead to
the formation of reactive spirocyclic iminium ion intermediate.
We wondered whether this intermediate would undergo a 1,2-
migration to give the indole, which is a well-known phenomenon
in indole chemistry.[15] However, treatment of the N1-methyl
substituted isocyanide 5k with NIS instead led to succinimide
adduct 10k by interception of the iminium ion intermediate by the
succinimide counterion. This product was stable upon
concentration, but decomposed slowly during chromatography.
We therefore opted to reduce the aminals 10k-o in situ to afford
spiroindolines 17. This transformation was not trivial, as several
competing decomposition pathways were observed. After some
optimization, we found that treatment with NH3•BH3 (5 eq.) in
MeOH led to selective reduction of aminals 10 to give
spiroindolines 17k-o in moderate to reasonable yields (29–60%).
Interestingly, we observed considerable induction (dr = 3:1) with
the N1 α-methylbenzyl-substituted isocyanide 5m, constituting
remarkable transfer of the rather distant chiral information and a
promising alternative for asymmetric catalysis.[16]
Scheme 6. Variations on the tryptamine isocyanide linker. Reaction
conditions: isocyanide 5 (1 mmol), NIS (1.05 mmol), CH2Cl2 (0.2 M); then
NH3•BH3 (5.0 mmol) in MeOH (0.1 M). [a] diastereomeric ratio based on 1H
NMR analysis.
Having
demonstrated
the
compatibility
of
the
iodospirocyclization with a wide variety of tryptamine-derived
isocyanides, we sought to apply our method to the synthesis of a
relevant
natural
product.
We envisioned that
19-
oxoaspidospermidine (25), an intermediate in the total synthesis
of aspidofractinine (3),[17] would be accessible in a few steps
from spirocyclization product 17i (Scheme 7). As nucleophilic
substitutions on the imidoyl iodide are possible (see thiol
substitution, Scheme 3), we envisioned intramolecular
nucleophilic attack of the ester enolate to construct the E ring.
Protection of the indoline nitrogen was essential, as addition of
LiHMDS immediately resulted in lactamization. This kinetically
favored pathway also limited the Boc protection, as the indoline
amine is not a strong nucleophile in its neutral form. By using an
excess of Boc2O with DMAP as an activating agent we were
able to overcome this problem, obtaining the protected indoline
22 in 62% yield (73% based on recovered starting material).
Subsequent treatment of 22 with LiHMDS resulted in clean
conversion to tetracycle 23 in 87% yield. Several groups have
previously shown the construction of the D ring from similar
tetracyclic frameworks in synthetic strategies toward related
indoline alkaloids.[4b,c,17b,c,18] Based on these precedents, we
chose to first reduce the enamine in 23, followed by dialkylation
with 1,3-diiodopropane. Standard reduction procedures initially
failed to convert the enamine. Fortunately, when we used NaBH4
as the reducing agent in a mixture of MeOH:TFA (4:1), the more
acidic solvent mixture facilitated the reduction, resulting in full
conversion within 5.5 hours.[19] We then used the conditions
reported by Dufour et al. to form the pentacyclic framework in a
two-step alkylation procedure.[17c] A single diastereoisomer of 24
was isolated, the relative configuration of which was confirmed
by 2D-NOESY experiments. Based on the 33% yield over these
two steps and the 1:1 selectivity of the similar enamine reduction
reported by Dufour et al.,[17c] we suspect our selectivity to be
derived from the instability of the undesired diastereomer. To
complete the total synthesis, the ethyl ester in 24 was converted
to the corresponding methyl ketone by treatment with TMSCH2Li,
after which TFA-mediated Boc deprotection afforded 19-
oxoaspidospermidine (25). The 1H NMR and 13C NMR spectra of
our synthetic sample fully matched the data reported by Dufour
et al.[17c]
Scheme 5. Scope of the N1 substituted tryptamine isocyanides. Reaction
conditions: isocyanide 5 (1 mmol), NIS (1.05 mmol), CH2Cl2 (0.2 M); then
NH3•BH3 (5.0 mmol) in MeOH (0.1 M). [a] Diastereomeric ratio based on 1H
NMR analysis. PMB = p-methoxybenzyl.
Finally, we evaluated substitution on the bridging ethylene
linker (Scheme 6). Initially, we did not expect the rigid
phenylene-bridged isocyanide 5p to produce the spirocyclic
framework. Pleasingly, however, we observed a clean 1H
spectrum after performing the reaction in CDCl3. In
a
subsequent experiment, the isocyanide was subjected to the
one-pot spirocyclization/ reduction procedure to generate C2-
symmetric spirobiindoline 20 in 59% yield. Subsequently,
tryptophan-derived isocyanide 5q was reacted under the same
conditions. While the iodospirocyclization products derived from
the comparable isocyanides 5a and 5p underwent complete
reduction after treatment with NH3•BH3, the spirocyclization/
reduction sequence of isocyanide 5q instead afforded
spiroindoline 21, leaving the imidoyl iodide unaffected. In
addition, we again observed some induction of stereochemistry,
albeit modest (dr = 1.5:1).
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Scheme 7. Formal total synthesis of (±)-aspidofractinine from spiroindoline 17i.
In conclusion, we have developed the iodospirocyclization
of a broad range of tryptamine-derived isocyanides 5. The
reaction is very fast and compatible with most organic solvents.
In addition, the reaction tolerates a wide variety of substituents
on the isocyanides, creating versatile synthetic intermediates
that can undergo various chemical transformations (Schemes 2
and 3). Spiroindoline 17i was converted in only six steps to 19-
oxoaspidospermidine, constituting a formal total synthesis of
aspidofractinine (3). We believe that the use of this methodology
on tailored isocyanides 5 should allow access to a wide variety
of other spiroindoline natural products.
[9]
[10] L. El Kaïm, L. Grimaud, P. Patil, Synlett 2012, 23, 1361–1363.
[11] N. A. Powell, J. T. Kohrt, K. J. Filipski, M. Kaufman, D. Sheehan, J. E.
Edmunds, A. Delaney, Y. Wang, F. Bourbonais, D.-Y. Lee, et al.,
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[12] Reactions involving either abstraction of the I atom (radical reaction) or
oxidative insertion of metals (e.g. Mg, Pd) in the C-I bond of imidoyl
iodides 11 led to rapid α-elimination, giving back isocyanides 5.
[13] Substituted isocyanides 5 are readily available via reductive coupling of
substituted indoles and N-acetylaminoacetaldehyde dimethyl acetal: a)
M. Righi, F. Topi, S. Bartolucci, A. Bedini, G. Piersanti, G. Spadoni, J.
Org. Chem. 2012, 77, 6351–6357. Isocyanide 5h was satisfyingly
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activation of the indole C2 position: b) M. Wegmann, M. Henkel, T.
Bach, Org. Biomol. Chem. 2018,16, 5376–5385.
Acknowledgements
We thank Jurriën Collet and Daniel Preschel for HRMS
measurements and Elwin Janssen for practical and NMR
support (all Vrije Universiteit Amsterdam). We thank the
Hercules Foundation (project AUGE/11/029 "3D-SPACE: 3D
Structural Platform Aiming for Chemical Excellence") for funding.
This work was financially supported by the Netherlands
Organisation for Scientific Research (NWO).
[14] N-Boc substituted 5 was completely consumed under the reaction
conditions, however, merely decomposition was observed.
[15] See, e.g.: K. G. Liu, A. J. Robichaud, J. R. Lo, J. F. Mattes, Y. Cai, Org.
Lett. 2006, 8, 5769-5771 and references cited therein.
[16] Our attempts to render the reaction asymmetric using various chiral
catalysts for electrophilic halocyclization only resulted in low ee’s
(≤15 %; see the SI for details).
[17] a) H. Kinoshita, T. Ohnuma, T. Oishi, Y. Ban, Chem. Lett. 1986, 15,
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Gramain, M. E. Sinibaldi, Y. Troin, H. P. Husson, J. Org. Chem. 1990,
55, 5483–5490.
Keywords: Alkaloids • cyclization • isocyanides • natural product
synthesis • spiroindolines
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Entry for the Table of Contents
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J. M. Saya, T. R. Roose, J. J. Peek, B.
Weijers, T. J. S. de Waal, C. M. L.
Vande Velde, R. V. A. Orru. E. Ruijter*
Page No. – Page No.
Iodospirocyclization of Tryptamine-
Derived Isocyanides: Formal Total
Synthesis of Aspidofractinine
I make(s) spirocycles: Iodospirocyclization of tryptamine-derived isocyanides
affords highly substituted spiroindolenine imidoyl iodides. The imine functionality
can undergo a variety of diastereoselective addition reactions, including in situ
reduction, while the imidoyl iodide functionality is remarkable stable. The utility of
the method was demonstrated by the formal total synthesis of (±)-aspidofractinine.
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