Rapid Access to 3-Acyl-5-alkoxybutyrolactams Using Triplet and Singlet Oxygen

Article abstract of DOI:10.1002/ejoc.201800832

A straightforward singlet oxygen-initiated cascade reaction sequence for the synthesis of a variety of key 3-acyl-5-alkoxybutyrolactams from furans has been developed.

Full text of DOI:10.1002/ejoc.201800832

A Journal of
Accepted Article
Title: Rapid Access to 3-Acyl-5-alkoxy-butyrolactams Using Triplet and
Singlet Oxygen
Authors: Manolis Sofiadis, John Sarris, Tamsyn Montagnon, Dimitris
Kalaitzakis, and Georgios Vassilikogiannakis
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800832
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10.1002/ejoc.201800832
European Journal of Organic Chemistry
COMMUNICATION
Rapid Access to 3-Acyl-5-alkoxy-butyrolactams Using Triplet and
Singlet Oxygen
Manolis Sofiadis, John Sarris, Tamsyn Montagnon, Dimitris Kalaitzakis* and Georgios
Vassilikogiannakis*
Dedication ((optional))
Abstract:
A
straightforward singlet oxygen-initiated cascade
found in many natural and unnatural products which have
interesting biological activities.3 Furthermore, these easy-to-
handle compounds are useful precursors for the synthesis of a
wide variety of other naturally occurring counterparts.4
reaction sequence for the synthesis of a variety of key 3-acyl-5-
alkoxy-butyrolactams from furans has been developed.
Although considerable efforts have been expended towards
achieving the synthesis of 5-hydroxy-butyrolactam frameworks,5
only a few of the resulting methodologies have also tackled
construction of the versatile 5-alkoxy congeners of type A
(Figure 1).3e,6,7 In the few examples dealing with the construction
of the corresponding 5-methoxy analogues,6,7 many synthetic
hurdles have been faced, mostly derived from their susceptibility
to hydrolysis and/or ring opening.6a,7b Moreover, a common
strategy is to use saturated lactams as precursors; however, this
approach imposes the need for additional derivatization steps in
order to introduce the ,-unsaturated moiety in a procedure
that necessitates protection of the lactam’s nitrogen.6 Thus,
there is a pressing need to develop a simple and general
method for the synthesis of compounds of type A (Figure 1)
starting from simple precursors.
Introduction
Natural products containing tetramic and non-tetramic
butyrolactam motifs are both ubiquitous and are of considerable
importance owing to their potent and diverse biological
properties.1,2 While the 5-hydroxy-butyrolactam unit dominates in
the family of natural tetramic and non-tetramic -lactams, its less
fragile 3-acyl-5-alkoxy counterpart of type A (Figure 1) can be
Results and Discussion
Herein, we demonstrate a straightforward and general protocol
for the synthesis of -acyl--alkoxy-butyrolactams starting from
readily accessible furans and molecular oxygen.8 Recently, we
developed a sustainable singlet oxygen-mediated methodology
Figure 1. Biologically active compounds containing the 3-acyl-5-alkoxy-
butyrolactam framework.
[]
M. Sofiadis, J. Sarris, Dr. T. Montagnon, Dr. D. Kalaitzakis, Prof. Dr.
G. Vassilikogiannakis
Department of Chemistry, University of Crete
Vasilika Vouton, 71003, Iraklion, Crete, Greece
E-mail: dkalaitzos@uoc.gr
E-mail: vasil@uoc.gr
http://www.chemistry.uoc.gr/vassilikogiannakis/
Dimitris Kalaitzakis: 0000-0002-3987-2653
Georgios Vassilikogiannakis: 0000-0002-9099-383X
ID:
Scheme 1. Envisioned scenario for the synthesis of 3-acyl-5-alkoxy-
butyrolactams 5.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201800832
European Journal of Organic Chemistry
COMMUNICATION
for the construction of -hydroxy--lactams of type III starting
from substituted furans I (Scheme 1).9 More specifically, the
photooxygenation (singlet oxygen) of simple furans followed by
addition of primary amines or ammonia, leads to the formation of
2-pyrrolidinones of type II (I → II, Scheme 1).8,10 The subsequent
oxidation of II, by a process where MB acts as a radical initiator
in the dark and triplet oxygen as the terminal oxidant, yields the
corresponding lactam III (II → III, Scheme 1).9 We envisioned
that these dual photosensitizing and redox activities of MB might
be exploited in the synthesis of the privileged 3-acyl-5-alkoxy-
buryrolactam scaffolds 5 as is illustrated in Scheme 1. This
would require the inclusion of more, and, potentially disrupting,
functionality in the starting furans. Thus, furans of type 1,
bearing an unprotected pendent hydroxyl group (present on the
4-substituent of the furan), would need to be transformed to the
corresponding -hydroxy--lactams 3. The acid induced
alcoholysis of 3 to the corresponding compound 4, followed by
its oxidation, would then be required to reach the desired
polysubstituted -acyl--alkoxy-,-unsaturated--lactams 5. For
excellence, the entire protocol going from furan to lactam
product (1 → 5) should be amenable to operation as a one-pot
process.
most efficient, since the desired 3-acyl-5-methoxy-butyrolactam
5aa was produced in 82% isolated yield after just 15 min
reaction time (conditions C, Scheme 2). Most importantly, these
optimal oxidation conditions could be applied smoothly without
purification of compound 4aa. In this instance, the solvent
methanol was simply replaced with CH2Cl2 prior to the DMP
addition, with the result that the full one-pot oxidation reaction
sequence gave the final product 5aa directly, in 65% overall
yield, starting from the corresponding furan 1a (Scheme 2).
After the optimal conditions had been found and validated,
various substituted furans, which would yield the motifs seen in
the molecules of biological interest, were tested in order to
explore the scope and limitations of the newly developed
synthetic protocol. Starting from substrates 1a-1d, the reactions
efficiently afforded the desired products 5aa-5da regardless of
the R1 and R2 substituents (52-74% yield, Scheme 3). In the
case of furans 1e and 1f, bearing bulkier R1 substituents, an
increase in the amount of ammonia (2 equiv., 3 h), and,
consequently, also of TFA (1.2 equiv., 15 min) proved essential
for the formation of the intermediate lactams of type 4 (Scheme
1). The subsequent oxidation was, once again, accomplished
using DMP (15 min) to furnish the corresponding compounds
5ea and 5fa in 56% and 58% yield respectively. The isolated
yields may be considered highly satisfactory since six discrete
transformations are contiguously incorporated in this tandem
reaction sequence.
The investigation began with the easily accessible furan 1a
(see Supporting Information for the facile preparation of the
furan precursors) which was subjected to established
photooxygenation conditions (Scheme 2). More specifically, the
substrate in methanol and in the presence of oxygen (bubbled
through the solution) and catalytic amounts of MB (3 mol%) was
subjected to visible irradiation (2 min). This photooxygenation
step was followed by treatment of the resultant adduct with, first
Me2S (4 equiv., 30 min) and then ammonia (1.2 equiv., 3 h). This
tandem reaction sequence delivered the corresponding hydroxy
lactam 3aa which was immediately treated in-situ with
trifluoroacetic acid (0.4 equiv.) for just 15 min. Gratifyingly, the
reaction gave the desired methoxylated product 4aa with an
exceptional isolated yield of 85%. With 4aa in hand, various
oxidation conditions for the preparation of the targeted
compound 5aa were investigated. Amongst the oxidants tested,
Dess-Martin periodinane (DMP, 1.1 equiv.) proved to be the
Scheme 3. Synthesis of 3-acyl-5-methoxy-butyrolactams 5 from furans and
ammonia. [a] Starting from the benzyl-substituted furan 1c, the optimal total
yield of 5ca (52%) was obtained when the photoxidation was undertaken using
rose Bengal instead of MB. In this case, MB was then added after the addition
of NH3 (see SI).
In an effort to expand the synthetic utility of the new
methodology, the investigation was continued using various
primary amines, instead of ammonia. Retaining methanol as the
solvent, the incorporation of primary amines 2b-2d (1 equiv.)
was not found to impede the reaction sequence from forming the
Scheme 2. Optimization of the conditions for the synthesis of 5aa.
desired 5-methoxy-butyrolactams of type
5 (Scheme 4).
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10.1002/ejoc.201800832
European Journal of Organic Chemistry
COMMUNICATION
Crucially, however, a simple alteration to the amount of TFA (1
equiv.) was essential for the implementation of the methanolysis
step, which was then completed within 4 h. The DMP oxidation
part of the tandem sequence led to the final 3-acyl-5-methoxy-
butyrolactams 5ab, 5ac and 5bd in 55-73% total isolated yield
(Scheme 4).
heavily adorned lactam cores from many biologically active
alkaloids (Figure 1).
Conclusions
Naturally occurring ,-unsaturated--acyl--alkoxy--lactams
alongside their synthetic congeners make up an important class
of alkaloids of biological interest. However, they are also
relatively fragile compounds richly adorned with functionality
whose synthesis can, therefore, be quite complex. We have
developed a new and highly effective methodology for the
synthesis of these lactams, which starts from readily accessible
furans. The operationally simple one-pot method is initially
choreographed by singlet oxygen, but also later uses ground
state oxygen (triplet oxygen) and is reliant throughout upon
methylene blue which acts in dual catalytic roles; first as a
sensitizer and then as a redox agent and radical initiator in the
dark.
Experimental Section
Supporting Information (see footnote on the first page of this article):
Experimental procedures, and compound characterization data (1H NMR,
13C NMR). This material is available free of charge in the Supporting
Information.
Scheme 4. Synthesis of various 3-acyl-5-alkoxy-butyrolactams of type 5 or 6
from furans and primary amines or ammonia.
Acknowledgements
The ability to adapt the cascade reaction sequence in order
to install different alkoxy groups at the 5-position of the lactam
moiety was also highly pertinent due to the presence of such
variation in the biologically active molecules of interest (Figure 1).
To this end, we studied the alcoholysis procedure using 1-
butanol as the alkoxy source. Specifically, starting the process
using furan 1b, and, ammonia (1.2 equiv.), consistently gave the
corresponding lactam of type 3 (Scheme 1). Then, by simply
replacing the solvent (MeOH) with 20 equiv. of 1-butanol, TFA
(0.1 equiv.) could be used to catalyse the alcoholysis step which
was completed within 24 h. The lower amount of TFA required
here in comparison to the previous methanolysis procedure
(Scheme 3, 0.4 equiv. of TFA) can be attributed to the removal
of excess ammonia during the solvent exchange. The DMP
oxidation in CH2Cl2 was also efficiently accomplished, affording
lactam 6ba in 55% isolated yield. Using benzyl amine (2c) and
starting the reaction sequence with substrate 1d the synthetic
protocol also proceeded as expected. In agreement with the
previous examples where primary amines had been used
(compounds 5ab, 5ac and 5bd, Scheme 4), the amount of TFA
had to be increased (2 equiv.) in order to achieve the completion
of the alcoholysis step (24 h). Finally, compound 6dc was
produced in 70% overall yield after the DMP oxidation.
Consequently, it has been shown that by auspicious choice of
the nitrogen, as well as, of the alkoxy source, access to the
entitled privileged scaffolds can readily be achieved. Most
importantly, many of the synthesized frameworks displayed in
Schemes 3 and 4 have all the correct structural features of the
The research leading to these results has received funding from
the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007-2013)/ERC grant
agreement no. 277588. We thank the Greek General Secretariat
of Research and Technology for matching (reward) funds (KA:
4143). We also thank the Alexander S. Onassis Public Benefit
Foundation for the Ph.D. fellowship of Manolis Sofiadis (G ZM
063-1/2016-2017). We are thankful to the ProFI (Proteomics
Facility at IMBB-FORTH) for performing all the HRMS analyses.
Keywords: methylene blue • triplet oxygen • singlet oxygen •
butyrolactams • furans
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European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Synthetic methodology*
Manolis Sofiadis, John Sarris, Tamsyn
Montagnon, Dimitris Kalaitzakis* and
Georgios Vassilikogiannakis*
Page No. – Page No.
A new and highly effective methodology for the synthesis of 3-acyl-5-alkoxy-
butyrolactam units from readily accessible furans, has been developed. The
operationally simple one-pot method is initiated by singlet oxygen, but also later
uses ground state oxygen (triplet oxygen) and is dependent by methylene blue
which acts in dual roles; first as a sensitizer and then as a radical initiator in the
dark.
Rapid Access to 3-Acyl-5-alkoxy-
butyrolactams Using Triplet and
Singlet Oxygen
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