One-Pot Transformation of Furans into 1-Azaspirocyclic Alkaloid Frameworks Induced by Visible Light

Article abstract of DOI:10.1021/acs.orglett.1c01661

High-value 1-azaspirocyclic scaffolds have been made from simple and readily accessible furan precursors in a single operation. The protocol is a one-pot sequence using highly sustainable conditions (oxygen, visible light, and a favored green solvent) that leads to a dramatic increase in molecular complexity. The initial substrates can include functionalities that are suitable for further elaboration; in this way, the pruned polycyclic skeletons of the stemonamine, cylindricine, and lepadiformine natural products were rapidly accessed.

Full text of DOI:10.1021/acs.orglett.1c01661

pubs.acs.org/OrgLett
Letter
One-Pot Transformation of Furans into 1‑Azaspirocyclic Alkaloid
Frameworks Induced by Visible Light
Stela Hoxha,† Dimitris Kalaitzakis,† Artemis Bosveli, Tamsyn Montagnon,
and Georgios Vassilikogiannakis*
Cite This: Org. Lett. 2021, 23, 5354−5358
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ABSTRACT: High-value 1-azaspirocyclic scaffolds have been
made from simple and readily accessible furan precursors in a
single operation. The protocol is a one-pot sequence using highly
sustainable conditions (oxygen, visible light, and a favored green
solvent) that leads to a dramatic increase in molecular complexity.
The initial substrates can include functionalities that are suitable
for further elaboration; in this way, the pruned polycyclic skeletons of the stemonamine, cylindricine, and lepadiformine natural
products were rapidly accessed.
or synthesis to remain relevant and keep pace with the
rapidly changing landscape of the chemical sciences, two
(through formation of the highly electrophilic N-acyliminium
ion9) or as nucleophiles at the β-carbon during inter- or
intramolecular reaction sequences.10,11 Using these two
different reactivities, we have been able to synthesize a diverse
array of nitrogen-containing polycycles (II−IV via paths a−c in
Scheme 1A).10,11 Homing in on one of these pathways in
particular, we found that path b yielded various spirocyclic
motifs of type III. These compounds were formed when a
pendent nucleophile reacted with the N-acyliminium ion that
had been generated at the γ-carbon of I through acid
catalysis.11 The umpolung concept that we wished to test
would see the γ-carbon’s reactivity reversed so that it behaved
as a nucleophile in spirocyclization reactions (Scheme 1B).
The reversal would be achieved by harnessing it as a
vinylogous enolate in a novel intramolecular addition
reaction12 under basic conditions, and the products would be
1-azaspiro[4.4]nonane or 1-azaspiro[4.5]decane frameworks
[C → 3 or 4 (Scheme 1C)].
The 1-azaspiro[4.4]nonane and 1-azaspiro[4.5]decane
motifs are present in an important and large subclass of
spirocyclic natural products that have significant pharmaceut-
ical relevance and that all have the nitrogen atom at the
junction between two fused rings (Figure 1).13 To date, rapid
access to these frameworks has proven to be challenging,14 and
furthermore, a strategy that has the flexibility to access both
ring patterns has remained elusive.15,16 The concomitant
generation of the two rings that make up the spirocycle in one
F
distinct components must be considered. First, targets should
be chosen very carefully. Random exploration of chemical
space in search of bioactive drug candidates is not an effective
strategy;1 instead, targeting pruned natural product skeletons
takes advantage of thousands of years of structural refinement
through evolution1 and promotes the requisite dominance of
sp3 centers (the “escape from flatland” theory that showed that
increasing the proportion of sp3 centers led to enhanced
activity).2 Thus, core frameworks from natural products make
excellent targets and arguably constitute the best starting point
for any structure−activity relationship (SAR) study. Second,
efficiency yields greater sustainability, and this has to be a
priority in every synthetic design. This goal requires us to
achieve rapid increases in molecular complexity (step
economy3) and to avoid, or at least minimize, nonproductive
steps (use of protecting groups4 and functional group
interconversions5). Using one-pot cascade reaction sequences6
is one of the most potent ways we can meet these rigorous
strictures, not only because of the number of bonds that can be
formed in a single operation (be it tandem, domino, or
telescoped in nature6) but also because they generate reactive
functionalities as and when they are needed; thus, they innately
reduce the requirement for protecting groups and separate-step
functional group interconversions. With these guiding
principles in mind, we set out to design a new one-pot process
that would take simple and relatively flat substrates and
transform them into key spirocyclic7 alkaloid skeletons, one
that would also make use of an interesting example of
umpolung that we will describe below.
Received: May 17, 2021
Published: June 28, 2021
A recent focus in our research has been exploring the
reactivity of 4-pyrrolin-2-ones of type I, which, as it turns out,
is remarkably versatile (Scheme 1).8 We have shown how
compounds of type I can act as electrophiles at the γ-position
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proposing could generate the 1-azaspiro[4.4]nonane and 1-
azaspiro[4.5]decane frameworks in a single synthetic oper-
ation. Moreover, this method affords the opportunity to
incorporate functional groups at selected positions on the
framework that would give rapid access, upon further
elaboration, to the polycyclic frameworks present in a large
range of natural products (Figure 1).
Scheme 1. Blueprint of the Rationale for the One-Pot
Transformation of Furans (1 or 2) into 1-Azaspirocyclic
Frameworks (3 or 4, respectively)
Our plan involved the construction of the entire framework
in a single step via a multielectrophile of type A, which is the
photooxygenation product of a readily accessible 2-substituted
furan [1 or 2 (Scheme 1C)].19 Achieving the controlled
reaction of A with a primary amine to give lactam B might
seem like an optimistic scenario given the proliferation of
electrophilic centers in this reactive intermediate; however,
many of the alternative reactions are reversible, and we hoped
that the sequence would coalesce at lactam B after an
irreversible amide bond formation. Using a slight excess of this
primary amine would also leave a small amount available to
catalyze the next step, the proposed vinylogous Michael
addition (B → aromatic enolate C → 3 or 4).
To test the hypothesis, we performed initial studies with the
easily synthesized furyl aldehyde 1a (see the Supporting
Information). The reaction sequence began with the photo-
oxygenation of 1a in MeOH using rose Bengal (RB) as a
photosensitizer (Scheme 2). To our delight, following the
Scheme 2. One-Pot Synthesis of 1-Azaspirocyclic
Compounds of Type 3 from Furans of Type 1
intermediate hydroperoxide’s reduction with Me2S (DMS) and
the subsequent addition of benzyl amine (1.1 equiv),
formation of 1-azaspirocyclic [4.4]nonane product 3a was
seen after 2 h. The intermediate 4-pyrrolin-2-one of type B was
not observed, suggesting that the vinylogous Michael addition
occurred instantaneously. Product 3a was isolated in 66% yield
with high diastereoselectivity (dr = 9/1). The relative
configuration was assigned by NOE correlations (see the
Supporting Information). Different solvents for the latter
stages of the sequence (from the addition of the amine
Figure 1. Alkaloids containing the 1-azaspirocyclic [4.4]nonane and
[4.5]decane motifs.
step is seen as being particularly demanding.17 One established
methodology that has been able to construct both rings of an
1-azaspirocyclic unit via a single synthetic operation is the aza-
Piancatelli rearrangement.18 However, this methodology is
limited because it cannot construct 1-azaspiro[4.5]decane
frameworks of type 4. In contrast, the methodology we are
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onward) were surveyed; iPrOH, CH3CN, THF, and DCM
were all tested. Of these solvents, it was found that only the
alcohols were effective, and the greater steric demand exerted
by iPrOH in comparison to MeOH led to a retardation of the
reaction rate (the reaction in iPrOH was not completed even
after 12 h). Thus, MeOH was confirmed as the optimum
solvent for the entire sequence with no switch in solvent
required at any stage. Presumably, alcohols are essential
because they assist in the formation and/or stabilization of the
vinylogous enolate of type C (Scheme 1C) through hydrogen
bonding networks. Studies were also performed to discover the
optimal amount of the amine. Increasing the amount of the
amine (1.5 equiv) led to the formation of byproducts derived
from the further reaction of 3a with the excess amine. On the
contrary, lower rates were observed by decreasing the amount
of the amine (0.9 equiv). In this case, analysis of the product
mixture revealed that alongside formation of 3a there remained
unreacted intermediate of type A (after 12 h), providing
further evidence that the intramolecular vinylogous Michael
reaction (B → 3 or 4) is very fast. In the next stage, these
optimized conditions were applied to various combinations of
furans (1a−1c) and amines (benzyl amine, allyl amine,
propargyl amine, and 3,4-dimethoxyphenethyl amine). In
every case, the desired products 3b−3h were produced in
good isolated yields (55−67%) with high diastereomeric ratios
[7/1−9/1 (Scheme 2)].
to increased production of byproducts. The optimized
conditions were then applied to various combinations of
furans (2a−2c) and amines (allyl amine, propargyl amine, and
3,4-dimethoxybenzyl amine), and in every case, the reaction
afforded the desired products 4b−4e in good yields (50−60%)
with moderate dr ratios [3.2/1−4/1 (Scheme 3)]. The reversal
of diastereoselectivity for the spirocycles of type 4 compared
with spirocycles of type 3 can possibly be attributed to the
greater stability of the 1,1,2-trisubstituted cyclohexane ring in
which the large 1,2-substituents are diequatorial (trans
diastereoisomer).
With rapid and efficient access to either of the two desired
spirocycles (3 or 4) now achieved, we next wanted to show
how amenable the newly developed methodology was to
elaborations that would target important polycyclic alkaloid
skeletons (Scheme 4). More specifically, starting from allyl-
Scheme 4. Synthesis of the Key Tricyclic Frameworks of
Naturally Occurring Bioactive Alkaloids
To synthesize 1-azaspirocyclic[4.5]decane motifs of type 4,
we next tested furyl aldehyde 2a in the reaction sequence
(Scheme 3). The results were similar to those of the first study
Scheme 3. One-Pot Synthesis of 1-Azaspirocyclic
Compounds of Type 4 from Furans of Type 2
substituted compound 3b, which had been made using the new
protocol, we performed a Wittig olefination (CH3P+Ph3I−/
nBuLi) followed by an olefin metathesis (second-generation
Grubbs catalyst in refluxing DCM). This simple sequence
yielded the stemonamine scaffold in 52% overall yield from 3b
(Scheme 4A). Next we focused on obtaining the entire
polycyclic frameworks of the cylindricine and lepadiformine
alkaloids (Scheme 4B). In this case, we separately harnessed
each of the two diastereomers of spirocyclic compound 4e to
synthesize both targeted frameworks through a common
synthetic route. Following their facile separation, each of the
two diastereomers of compound 4e was subjected to reduction
using NaBH4 followed by dehydration (catalyzed by PTSA) to
yield the olefin substrate (cis-4e → 7 and trans-4e → 8) for a
Grubbs metathesis reaction. The overall isolated yield for these
two steps was 63% for 7 and 75% for 8. These two compounds
(7 and 8) were next separately subjected to a second-
generation Grubbs catalyst at reflux (DCM for 7 and toluene
for 8). The intact tricyclic skeleton of the cylindricines was
obtained in the reaction starting from 7 and of the
lepadiformines in the one starting from 8 with isolated yields
in which the same conditions were applied; namely, with the
addition of benzyl amine (1.1 equiv) to the reaction solution in
MeOH, the desired product 4a was formed, albeit at a slower
rate (the reaction required 24 h to reach completion), with an
isolated yield of 55%. The diastereomeric ratio for the product
was 3.5/1. Increasing the amount of amine employed, once
again, did not improve the sequence’s outcome but instead led
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of 62% and 65%, respectively. Arriving at these complex
polycyclic frameworks with such speed and with such a high
overall yield greatly facilitates the access to these families,
which is required for them to be studied further.
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With this work, we have shown that the reactivity of the γ-
carbon of 4-pyrrolin-2-ones can be reversed from its better
known behavior as an electrophilie (via the corresponding N-
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01661.
Full experimental details and spectral data (PDF)
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G. The Reticent Tautomer: Exploiting the Interesting Multisite and
Multitype Reactivity of 4-Pyrrolin-2-ones. Org. Biomol. Chem. 2020,
18, 180−190.
AUTHOR INFORMATION
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Corresponding Author
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Georgios Vassilikogiannakis − Department of Chemistry,
University of Crete, 71003 Iraklion, Crete, Greece;
orcid.org/0000-0002-9099-383X; Email: vasil@uoc.gr
Authors
Stela Hoxha − Department of Chemistry, University of Crete,
71003 Iraklion, Crete, Greece
Dimitris Kalaitzakis − Department of Chemistry, University of
Crete, 71003 Iraklion, Crete, Greece; orcid.org/0000-
0002-3987-2653
Artemis Bosveli − Department of Chemistry, University of
Crete, 71003 Iraklion, Crete, Greece
Tamsyn Montagnon − Department of Chemistry, University
of Crete, 71003 Iraklion, Crete, Greece
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01661
Author Contributions
†S.H. and D.K. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research leading to these results has received funding from
the Greek General Secretariat of Research and Technology in
the form of matching (reward) funds (KA: 4143, KA: 4154,
and KA: 10379). The authors thank the Mass Spectrometry
Facility of the University of Crete for obtaining the HRMS
data.
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