Activating Imides with Triflic Acid: A General Intramolecular Aldol Condensation Strategy Toward Indolizidine, Quinolizidine, and Valmerin Alkaloids

Article abstract of DOI:10.1021/acs.orglett.9b04199

A simple, inexpensive, step economic, and highly modular synthetic strategy to access izidine alkaloids is described. The key step is a TfOH-promoted intramolecular aldol condensation between enol and cyclic imide moieties. This cyclization strategy can be employed within an aza-Robinson annulation framework and represents a general tool to build fused bicyclic amines. To illustrate the power of this method, we describe the preparation of (±)-coniceine, (±)-quinolizidine, (±)-tashiromine, (±)-epilupinine, and the core of (±)-valmerins.

Full text of DOI:10.1021/acs.orglett.9b04199

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Activating Imides with Triflic Acid: A General Intramolecular Aldol
Condensation Strategy Toward Indolizidine, Quinolizidine, and
Valmerin Alkaloids
,‡
Yovanny Quevedo-Acosta,†,‡ Igor D. Jurberg,*,† and Diego Gamba-Sanchez*
́
†Institute of Chemistry, State University of Campinas, Rua Monteiro Lobato 270, 13083-862 Campinas, Sao
̃
Paulo, Brazil
‡Laboratory of Organic Synthesis, Bio and Organocatalysis, Chemistry Department, Universidad de los Andes, Cra 1 No. 18A-12
́
Q:305, 111711 Bogota, Colombia
S
* Supporting Information
ABSTRACT: A simple, inexpensive, step economic, and
highly modular synthetic strategy to access izidine alkaloids is
described. The key step is a TfOH-promoted intramolecular
aldol condensation between enol and cyclic imide moieties.
This cyclization strategy can be employed within an aza-
Robinson annulation framework and represents a general tool
to build fused bicyclic amines. To illustrate the power of this
method, we describe the preparation of ( )-coniceine,
( )-quinolizidine, ( )-tashiromine, ( )-epilupinine, and the
core of ( )-valmerins
Numerous approaches aiming at specific alkaloids have
lkaloids are one of the most important nitrogen-
1
Acontaining compounds found in nature. Among them, typically relied on long reaction sequences. However, being
able to use a general strategy to access a large number of these
alkaloids in short reaction sequences and in high yields is
highly desirable, but remains until today an unmet challenge.
Among the synthetic approaches toward indolizidine and
quinolizidine alkaloids, a number of them are based on
cyclization strategies of nucleophilic moieties onto cyclic
imides, often leading to condensation-type intermediates.14,15
For instance, Flitsch and Pandl reported an intramolecular
Wittig reaction converting phosphorus ylide 1 into bicycle 2
(Scheme 1a);14a−c Svete and coauthors described the
conversion of methyl ketone 3 into the condensed product 4
via a nucleophilic attack of an enamine intermediate generated
from the use of N,N-dimethylformamide dimethyl acetal
(DMFDMA) onto the carbonyl group of the succinimide
ring (Scheme 1b).14d Szostak and coauthors reported a SmI2-
promoted reduction of imides (via SET), followed by
intramolecular cyclization of the resulting radical anion onto
an olefin moiety to convert compounds of type 5 into bicycles
6 (Scheme 1c),14e−g and Hsung and coauthors described a
BF3·OEt2-promoted intramolecular cross-metathesis reaction
to convert ynamides 7 into bicycles 814h (Scheme 1d).
approximately 30% of all known natural alkaloids are fused
azabicyclic systems known as izidine alkaloids.2 In the past
decades, a particular interest has been paid to indolizidine and
quinolizidine families3 (Figure 1).
Figure 1. Examples of bioactive indolizidine and quinolizidine
alkaloids.
Several of these alkaloids display prominent biological
activities3,4 such as antitumoral,5 antimicrobial,6 and modu-
lation power of sodium channels,7 among other functions, and
are widespread in plants,6b,8 fungi,9 insects,10 and most notably
in frogs.11 Arguably, as a consequence of this abundance,
indolizidine and quinolizidine alkaloids show a rich structural
diversity; their family members have attracted the attention of
numerous researchers over the years, and several synthetic
strategies describing their preparation have been devel-
oped.12,13
Based on our own careful analysis of potential strategic
disconnections aimed at the preparation of bicycles 10, we
reasoned that intramolecular aldol condensations between an
enolizable carbonyl fragment and an activated imide ring of a
starting substrate 9 could be a highly attractive approach
Received: November 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04199
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Presentation of a Selection of Previous Methods
and Current Work
Table 1. Optimization of Reaction Conditions
a
entry
solvent
promoter
T (°C)
14 (%)
1
2
3
4
5
6
7
8
9
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
MeOH
MeCN
Sc(OTf)3 (1 equiv)
aniline (1 equiv)
pyrrolidine (1 equiv)
TfOH (1 equiv)
TfOH (1 equiv)
TfOH (1 equiv)
TfOH (1 equiv)
TfOH (1 equiv)
TfOH (0.4 equiv)
TfOH (1.5 equiv)
83
83
83
83
65
82
77
90
90
90
26
traces
15
70
NR
NR
40
90
14
AcOEt
toluene
toluene
toluene
10
71
a
Isolated yields. NR: no reaction.
14 in a higher 90% yield (Table 1, entry 8). Further attempts
considering a lower loading (0.4 equiv, Table 1, entry 9) or a
higher loading (1.5 equiv, Table 1, entry 10) of TfOH did not
afford improved yields (14 and 71%, respectively, see also the
Supporting Information for more details).
With the optimal reaction conditions for the desired
intramolecular aldol condensation event in hand, we moved
forward to the total synthesis of indolizidine and quinolizidine
alkaloids.
Our first target was ( )-coniceine. The synthesis starts with
an aza-Michael addition of succinimide 11 onto MVK 12 in
the presence of EtONa to afford intermediate 13 in
quantitative yield, which was then followed by our protocol
for the TfOH-promoted intramolecular aldol condensation,
thus affording bicycle 14 in 90% yield. Overall, this two-step
sequence can be regarded as an aza-Robinson annulation, and
it could be performed in gram-scale without any significant loss
in yield. We anticipate that this method can be valuable for the
preparation of a number of fused bicyclic amines.
At this stage, attempts were made to reduce intermediate 14
(e.g., L-selectride and DIBAL-H), but mixtures of unidentified
products were obtained. Nevertheless, we could establish a
protocol to fully reduce the enone moiety of 14 via
hydrogenation in the presence of Pd/C as catalyst and a
solvent system of 1 M HCl in EtOH to afford 15, thus avoiding
the need for an additional Wolff−Kishner reduction step of a
remaining ketone group. Our working hypothesis for the
mechanism of this transformation is that under these reaction
conditions, the ketone group is reduced to the alcohol,
followed by a dehydration step to afford an olefin that is also
hydrogenated, overall leading to a fully saturated chain.18
Finally, a straightforward reduction of amide 15 can be made
using LiAlH4 to produce the desired product, ( )-coniceine
16, in quantitative yield. Overall, this alkaloid was prepared in
only 4 steps in 79% yield (Scheme 2). To the best of our
knowledge, this is currently the shortest synthetic route
described for this target.
(Scheme 1e). If this transformation is preceded by an aza-
Michael addition of the cyclic imide onto a methyl vinyl ketone
derivative, then one would have in hand an invaluable aza-
Robinson annulation strategy16 which would allow the
construction of the bicyclic core of indolizidine and
quinolizidine alkaloids in only two steps.
At the outset, the aza-Michael addition of succinimide 11
onto methyl vinyl ketone (MVK) 12 could be readily
accomplished in good yields in the presence of several bases
(e.g., 4-DMAP 90%, DBU 85%, K2CO3 88%).17 However, we
were able to obtain a quantitative yield for the corresponding
adduct 13 using EtONa. This has set the stage for the
optimization of our desired intramolecular condensation
reaction, aiming at converting 13 to bicycle 14.
Initial investigation employing Sc(OTf)3 (1 equiv) as Lewis
acid in 1,2-DCE at 83 °C demonstrated the feasibility of our
approach: 14 was obtained in 26% yield (Table 1, entry 1). We
evaluated also an alternative strategy employing aniline (Table
1, entry 2) and pyrrolidine (Table 1, entry 3) as promoters (1
equiv) in 1,2-DCE at 83 °C, but these preliminary experiments
were not encouraging, as only traces and 15% yield of 14,
respectively, could be obtained. To our delight, when we
evaluated the use of a strong Brønsted acid, TfOH (1 equiv),
again in 1,2-DCE at 83 °C, 14 could be produced in a good
70% yield (Table 1, entry 4). Encouraged by this promising
result, we turned our attention to the use of TfOH in the
presence of different solvents: MeOH at 65 °C (Table 1, entry
5) and MeCN at 82 °C (Table 1, entry 6) did not afford any
productive reaction; AcOEt at 77 °C produced 14 in a lower
40% yield (Table 1, entry 7), and toluene at 90 °C produced
A natural extension of this strategy was to use other cyclic
imides, and we questioned ourselves whether glutarimide 17
could be also employed for the total synthesis of the alkaloid
( )-quinolizidine 22 in similar efficiency. This time, the two-
step sequence for our aza-Robinson annulation protocol
involving glutarimide 17 and MVK 12 afforded the
corresponding bicycle 19 in quantitative yield. Subsequent
B
DOI: 10.1021/acs.orglett.9b04199
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Total Synthesis of ( )-Coniceine
Scheme 4. Cyclization Using Ketals
TfOH in toluene at 90 °C to afford intermediate 29. This
compound is unstable and cannot be isolated. Therefore, we
opted to carry out a sequential reduction step using LiAlH4,
which allowed us to successfully obtain the desired alkaloid,
( )-tashiromine 30, in combined 54% yield (Scheme 5).
hydrogenation in the presence of Pd/C as catalyst and the
solvent mixture 1:1 EtOH:HCl 1 M proved more challenging:
the reaction takes longer, and a mixture of bicyclic amides 20
and 21 is produced in 73 and 27% yields, respectively.
Nevertheless, both compounds can be isolated by flash column
chromatography, and bicycle 21 can be further reduced to 20
in 80% yield using a Wolff−Kishner protocol. Finally, LiAlH4-
promoted reduction of intermediate 20 leads to ( )-quinoli-
zidine 22 in 93% yield (Scheme 3).
Scheme 5. Total Synthesis of ( )-Tashiromine
Scheme 3. Total Synthesis of ( )-Quinolizidine
1,3-Dioxolanes have proven to be viable indirect synthetic
alternatives to the use of aldehydes in our aldol condensation
protocol. Our working hypothesis to explain such a success is
that a protonated 1,3-dioxolane is in tautomeric equilibrium
with an open oxonium form, which can readily undergo
tautomerization to unlock an enolether intermediate. This
enolether can undergo α-functionalization in the presence of
electrophiles, while also presenting an increased stability due to
the reversible formation back to the acetal form19 (see the
Supporting Information, Scheme S1). Indeed, careful analysis
Then, we turned our attention to the synthesis of more
functionalized indolizidines and quinolizidines, and we became
interested on the question whether in addition to methyl-
ketones, aldehydes could also undergo aldol condensations
under our optimal reaction conditions. If feasible, this would
allow us to target the preparation of ( )-tashiromine and
( )-epilupinine. Unfortunately, all our attempts to perform
this cyclization using aldehyde groups were unsuccessful. To
address this problem, we reasoned that ketals could be also
potentially viable reacting partners,19 and we verified our
hypothesis on the previous reaction sequences employed for
the preparation of ( )-coniceine and ( )-quinolizidine.
Indeed, ketals are competent functional groups for this
transformation, as they allowed the conversion of intermedi-
ates 23 and 24 to the corresponding bicycles 14 and 19 in
identical yields as the parent ketones, 90 and 99% yields,
respectively (Scheme 4).
Having demonstrated the use of ketals as a viable synthetic
alternative, we advanced our plans to synthesize both
( )-tashiromine and ( )-epilupinine.
The synthetic route employed for the preparation of
( )-tashiromine starts with a Mitsunobu reaction involving
succinimide 11 and 5-hexen-1-ol 25 to afford the N-alkylated
intermediate 26 in 87% yield. Ozonolysis of 26 leads to the
corresponding aldehyde 27 in 92% yield, which is followed by
a protection reaction with ethylene glycol to produce acetal 28
in 94% yield. The key step of the synthesis is carried out with
1
of the H NMR spectrum of the crude mixture obtained from
the treatment of 28 with TfOH suggests the formation of the
parent acetal of 29.
The key condensation event is performed in the presence of
a strong Brønsted acid, TfOH [pKa(DMSO) ≈ −14],20 and
adventitious water, which is most likely responsible for the
hydrolysis of the acetal in the reaction mixture.
The LiAlH4 reduction of intermediate 29 presumably
converts the aldehyde group to a primary alcohol. The high
diastereoselectivity observed for ( )-tashiromine 30 (dr
>20:1) can be explained as a consequence of the OH-guided
LiAlH4-reduction of an iminium tautomer 31, which delivers
the hydride from the same face as the CH2OH chain21 (see the
Supporting Information, Scheme S2).
The next alkaloid targeted by this general platform was
( )-epilupinine. Its total synthesis starts with a Mitsunobu
protocol involving glutarimide 17 and 5-hexen-1-ol 25 to
afford the corresponding N-alkylated compound 32 in 92%
yield. Ozonolysis of 32 affords aldehyde 33 in 87% yield, which
is sequentially transformed into the corresponding acetal 34 in
91% yield using ethylene glycol and a catalytic amount of
PTSA. This set the stage for the key TfOH-promoted
intramolecular aldol condensation leading to intermediate 35.
C
DOI: 10.1021/acs.orglett.9b04199
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Organic Letters
Letter
The aldehyde intermediate 35 is directly reduced with LiAlH4
to afford ( )-epilupinine 36 in combined 49% yield and dr
>20:1 (Scheme 6).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04199.
Scheme 6. Total Synthesis of ( )-Epilupinine
Experimental procedures, full spectroscopic data, and 1H
and 13C NMR spectra of all compounds (PDF)
Accession Codes
CCDC 1967016−1967017 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, 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: ijurberg@unicamp.br.
Finally, we also were interested in the synthesis of
( )-valmerins due to their structural proximity to indolizidine
alkaloids and notable antitumoral activity.22 In addition, this
was an opportunity to evaluate the use of phthalimides 37 in
our intramolecular aldol condensation protocol. In this regard,
we aimed to prepare the tricyclic core of ( )-valmerins 41 as a
proof-of-principle.
This synthetic strategy starts with the Michael addition of
phthalimide 37 onto MVK 12, which was accomplished in
quantitative yield. Treatment of 38 with TfOH in toluene at 90
°C affords tricycle 39 in 94% yield. This intermediate was
hydrogenated using Pd/C as catalyst in 92% yield to afford
ketone 40; interestingly, the reduction of 39 with H2 and Pd/C
catalyst in the presence of HCl does not produce the direct
reduction of the enone moiety to the corresponding alkane
fragment, but rather stops at the ketone level. This observation
forced us to incorporate an additional Wolff−Kishner
reduction in the reaction sequence to afford the ( )-valmerins
core 4l in 74% yield (Scheme 7). Overall, the valmerins core
could be prepared in 70% yield and 4 steps.
*E-mail: da.gamba1361@uniandes.edu.co.
ORCID
Igor D. Jurberg: 0000-0002-1133-6277
́
Diego Gamba-Sanchez: 0000-0001-5432-5108
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Y.Q.-A acknowledges the Chemistry Department of Uni-
versidad de los Andes (UniAndes) for a PhD fellowship and its
Faculty of Science for providing financial support for an
internship. Financial support for this work was provided by the
Faculty of Science of UniAndes (INV-2018-48-1337) to Y.Q.-
A and D.G.-S., and a Fapesp Grant (2017/24017-0) was
awarded to I.D.J. The authors also greatly appreciate the
support of Dr. Deborah Simoni (Unicamp, Brazil) for X-ray
analyses and Dr. Mario Macias (UniAndes, Colombia) for
careful refinement of the X-ray structure of 39.
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Scheme 7. Synthesis of ( )-Valmerins Core
■
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DOI: 10.1021/acs.orglett.9b04199
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