A versatile synthesis of meyers' bicyclic lactams from furans: Singlet-oxygen-initiated reaction cascade

Article abstract of DOI:10.1002/anie.201204419

All in one: Meyers' bicyclic lactams were synthesized in high yield from furans using a new and powerful method that involves a one-pot singlet-oxygen-initiated reaction cascade (see scheme; TFA=trifluoroacetic acid). This method has broad synthetic potential because of the ease of access to a wide range of furans with a variety of substituents. Copyright

Full text of DOI:10.1002/anie.201204419

Angewandte
Chemie
DOI: 10.1002/anie.201204419
Synthetic Methods
AVersatile Synthesis of Meyersꢀ Bicyclic Lactams from Furans: Singlet-
Oxygen-Initiated Reaction Cascade**
Dimitris Kalaitzakis, Tamsyn Montagnon, Ioanna Alexopoulou, and
Georgios Vassilikogiannakis*
Dedicated to Professor K. C. Nicolaou
Ever since they were pioneered by Meyers the homochiral
bicyclic lactams[1,2] bearing his name (B, Scheme 1) have been
exceedingly popular and versatile scaffolds for the enantio-
selective construction of new stereogenic centers, including
the most challenging type, quaternary carbon centers. These
which has been extensively elucidated by Speckamp and
Hiemstra.[8] In this case, a succinimide intermediate is
substituted at the C5-position (usually by addition of
a Grignard reagent) and then undergoes intramolecular
cyclization under acidic conditions. Several domino reactions
affording specific bicyclic lactams have also been reported
recently,[9] as well as, other stepwise approaches to the
scaffold.[10] This unceasing interest in finding new syntheses
for the Meyersꢀ bicyclic lactams in itself provides testament to
the usefulness of the scaffold and the diversity of potential
applications there are for it.
Herein, we introduce a new and mild method for the
synthesis of a wide variety of Meyersꢀ bicyclic lactams. This
novel approach, which uses a singlet-oxygen-mediated reac-
tion cascade, is particularly powerful because the one-pot
reaction begins from furan substrates which can be variously
functionalized (A, Scheme 1) with ease, thus allowing direct
access to highly substituted scaffolds of type B (frequently
with excellent stereoselectivity). In this way, the new method
also exhibits a very high degree of step[11] and atom
economy[12] and utilizes the selective “green” reagent, singlet
oxygen, to achieve these rapid increases in molecular com-
plexity with precision and minimum production of waste
products, thereby attaining many of the recently established
criteria for an “ideal synthesis”.[13]
The idea for this new method was born from our
experience in the field of furan photooxygenations,[14] which
has taught us to regard the furan motif as a readily accessible
and easy-to-manipulate 1,4-enedione equivalent (or precur-
sor).[15] This fact led us to ask whether the intermediate C
(Scheme 2) could be intercepted by an 1,2-aminoalcohol, and,
subsequently rearrange and cyclize (under acid catalysis) to
afford the Meyersꢀ bicyclic lactams, without the need for
dehydrating conditions, or high temperatures, which have
traditionally been employed. This ambitious concept is
summarized, in mechanistic terms, in Scheme 2 (note: only
selected steps and intermediates are shown). Thus, when
a furan is oxidized upon exposure to singlet oxygen in MeOH,
intermediates of type C are known to form easily from the
in situ reduction (with Me2S) of a hydroperoxy functionality,
which is formed after the solvent-induced collapse of the
initially formed endoperoxide adduct has occurred.[14,15] We
hypothesized that addition of a 1,2-aminoalcohol at this stage
should regioselectively afford the aminal D (via the more-
stable, more-substituted oxonium cation). Aminal D would
ring open to imino enal E, as shown in Scheme 2, and then
ring close again to afford 2-pyrrolidinone G, via 2H-pyrrol-2-
Scheme 1. Generalized representation of the transformation achieved
with this new method. TFA=trifluoroacetic acid.
bicyclic lactams have been utilized in a myriad of different
ways in the synthesis of a wide variety of natural products[2,3]
and nonnatural molecules possessing interesting biological
activity,[2,4] and, also in a diverse array of other synthetic
endeavors.[2,5] The most general method for their synthesis,
introduced in the seminal work by Meyers et al.,[1,2] wherein
a g-ketoacid is condensed with an amino alcohol under
dehydrating conditions in toluene, heated to reflux, is still, by
far, the most commonly employed means of accessing the
bicyclic scaffold B. Modifications have been made to the
Meyersꢀ lactamization with the aim of introducing milder
conditions;[6] these modifications range from using microwave
energy[6a] or employing Lewis acid catalysis,[6b] to activating
the acid.[6c] A second commonly employed,[7] but stepwise,
route to these bicyclic lactams, also originating from the
Meyersꢀ group,[2a] relies heavily on N-acyliminium chemistry,
[*] Dr. D. Kalaitzakis, Dr. T. Montagnon, I. Alexopoulou,
Prof. Dr. G. Vassilikogiannakis
Department of Chemistry, University of Crete
Vasilika Vouton, 71003, Iraklion Crete (Greece)
E-mail: vasil@chemistry.uoc.gr
[**] We received funding for this research from the European Research
Council under the European Union’s Seventh Framework Pro-
gramme (FP7/2007-2013; ERC grant agreement no. 277588). We
thank the European Social Fund (ESF) and Greek National Strategic
Reference Framework (NSRF) for cofinancing a PhD fellowship for
I.A. by the Heracleitus II program. We also thank Prof. Robert
Stockman and George Procopiou for their help with the HRMS.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204419.
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Table 1: One-pot synthesis of various bicyclic lactams starting from furan
substrates.
Scheme 2. Mechanistic summary for the one-pot cascade reaction
sequence that transforms furans A into bicyclic lactams B.
ol F. It was hoped that addition of an acid at this point, would
affect the desired hydroxy acyl iminium cyclization to give the
corresponding bicyclic lactam (H!B) as the final product of
a one-pot reaction cascade.
Gratifyingly, despite the extraordinary complexity of the
designed reaction cascade, we were able to successfully
transfer this hypothesis into a working laboratory protocol
(Table 1). Thus, in the simplest case where 2-methylfuran was
oxidized with singlet oxygen,[16] in MeOH followed by in situ
reduction (Me2S) of the resultant hydroperoxide, and then by
the addition of 2-aminoethanol, and later catalytic TFA
(20 mol%), the desired corresponding Meyersꢀ bicyclic
lactam was obtained (entry 1).
With this proof of principle in hand, we set out to
systematically investigate the effect of varying both the furan
and 1,2-aminoalcohol substituents, and, concomitantly, delin-
eate the precise stereochemical outcomes of the reaction
cascade (Table 1). Commercially available furan starting
materials were used throughout except in the cases of 2-
benzylfuran (entries 2, 4, and 6) and the furan shown in
entry 7, where the requisite substrates were synthesized using
known procedures.[17] In general, the yields are good when the
large increase in molecular complexity that has been achieved
in this one-pot procedure is taken into consideration, and
given the intricate nature of the reaction cascade. With
regards to the stereochemical outcomes (confirmed by NOE
studies),[18] the presence of a defined stereogenic center
adjacent to the amino group (R4 attachment position) on the
[a] Yields are of the isolated products. [b] Separable diastereoisomers.
[c] Inseparable diastereoisomers.
1,2-aminoalcohol induces highly stereoselective formation of
the ring junction of the product (R1 attachment position in the
product B, Scheme 1), as can be seen in entries 3–10. In
contrast, when there is a defined stereogenic center adjacent
to the alcohol (R5 attachment position) on the 1,2-amino-
alcohol no significant stereoselectivity is achieved for the
2
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Angewandte
Chemie
overall reaction, as both ring-junction isomers are formed
(d.r. = 55:45, R1/R5 anti: R1/R5 syn, entry 11). Similarly,
substituents at the R2 and R3 positions of the furan substrate
are incorporated in the final bicyclic lactam products with no
significant stereoselectivity (d.r. = 55:45, R1/R3 anti: R1/R3
syn, entry 7; d.r. = 55:45, R1/R2 syn: R1/R2 anti, entry 8),
except in the case of menthofuran (entry 9), which differs as it
is bicyclic.
The following observations are also worthy of note. It has
been reported in the literature[19] that the product of the
reaction shown in entry 1, readily opens and reacts intermo-
lecularly to form the centrosymmetric dimer under aqueous
acidic conditions (Scheme 3). We found this to be true
In summary, we have introduced a new and versatile
method for the synthesis of Meyersꢀ bicyclic lactams using
a “green”, step- and atom-economic singlet-oxygen-initiated
reaction cascade. This method has broad synthetic potential
as it begins from simple furan substrates, which can be readily
synthesized and functionalized with various substituents, as
desired; a feature that contrasts with the limitations (both in
terms of their synthesis and subsequent handling and
purification) imposed by the g-ketoacid precursors used in
the traditional synthesis of Meyers et al.[1,2] Furthermore, the
cascade initiator, singlet oxygen, is an extremely selective
reagent conferring on its reactions very broad functional
group tolerance and a lack of need for protecting groups.[14]
For all these reasons, it is believed that this method will prove
to be a powerful addition to the synthetic chemistꢀs armory.
Received: June 7, 2012
Published online: && &&, &&&&
Keywords: nitrogen heterocycles · domino reactions ·
furan oxidation · Meyers’ bicyclic lactams · singlet oxygen
.
Scheme 3. Acid-catalyzed dimerization of bicyclic lactams.
(indeed, it also applied to other more heavily substituted
products, although to a lesser extent), but we also found that
this undesired dimerization could be avoided by moderating
the amount of TFA employed in the cyclization step, and, in
the most vulnerable cases, by neutralizing this TFA with Et3N
prior to concentration of the sample. In general, 20 mol% of
TFA was initially added and further additions (up to
a maximum of 60 mol%) were only made when deemed
necessary according to TLC analysis of the reaction mixture.
The TFA-catalyzed cyclization took between 1 to 9 hours to
reach completion. This tendency to dimerize may be the
reason that, somewhat counterintuitively, it would appear
that the bulkier the ring-junction R1 substituent is, the higher
the yields obtained are (entries 7 and 9). For other meth-
ods[10a] that proceed through intermediates of type G
(Scheme 2) it has been reported that these intermediates
were fleeting and could not be isolated and characterized;
however, though they cannot be described as stable, we have
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1
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In the case of entry 8, the two stereoisomeric final
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but subsequently proved to be highly susceptible to racemi-
zation (even on brief standing in CDCl3 solution) by the
opening up of the bicyclic lactam to the 2-pyrrolidinone
(analogous to intermediate G, Scheme 2) and subsequent
reclosure. Finally, and again related to intermediate G, when
2-benzylfuran was photooxidized and reacted with 2-amino-
ethanol, the yield was a mere 30% (entry 2) and the product
isolated was in equilibrium with an open form;[20] however,
when 2-aminoethanol is replaced with either (S)-serine ethyl
ester (entry 4), or (R)-phenylglycinol (entry 6), the product
yield improves dramatically to 59 and 58%, respectively,
presumably owing to the Thorpe–Ingold angle compression
effect favoring ring closure.
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[16] The furan substrate in MeOH at 08C with rose bengal (10ꢀ4 m),
added as photosensitiser, was exposed to irradiation from
a xenon Variac Eimac Cermax 300W visible-spectrum light for
a period of 8 min whilst oxygen was gently bubbled through the
reaction mixture.
[17] For synthesis of benzylfuran, see the Supporting Information for
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[20] The open form corresponds to intermediate G except that the
preferred 2-pyrrolidinone, in this instance, is that which places
the double bond exo from the five-membered ring and in
conjugation with the phenyl group, namely, 5-benzylidene-1-(2-
hydroxyethyl)pyrrolidin-2-one. The exact structure is given in
the Supporting Information.
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
D. Kalaitzakis, T. Montagnon,
I. Alexopoulou,
G. Vassilikogiannakis*
&&&& — &&&&
A Versatile Synthesis of Meyers’ Bicyclic
Lactams from Furans: Singlet-Oxygen-
Initiated Reaction Cascade
All in one: Meyers’ bicyclic lactams were
synthesized in high yield from furans
using a new and powerful method that
involves a one-pot singlet-oxygen-initi-
ated reaction cascade (see scheme;
TFA=trifluoroacetic acid). This method
has broad synthetic potential because of
the ease of access to a wide range of
furans with a variety of substituents.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!