Synthesis of 2-pyridones by cycloreversion of [2.2.2]- bicycloalkene diketopiperazines

Article abstract of DOI:10.1021/ol403632t

A general strategy for the conversion of [2.2.2]-diazabicyclic alkene structures to 2-pyridone aromatic heterocyclic products is reported. The reaction sequence starts from 2,5-diketopiperazine (DKP) derivatives, is compatible with both aromatic and aliphatic aldehyde components, and can intercept either intra- or intermolecular cycloaddition manifolds. Priming of one aza-bridging function in the intermediate [2.2.2]-DKP scaffold permits cycloreversion (microwave heating) and selective extrusion of cyanate derivatives leading to the formation of 2-pyridone structures. Progress toward the synthesis of louisianin A and B, antiproliferative 2-pyridone natural products, is also disclosed.

Full text of DOI:10.1021/ol403632t

Letter
pubs.acs.org/OrgLett
Synthesis of 2‑Pyridones by Cycloreversion of [2.2.2]- Bicycloalkene
Diketopiperazines
Kaila A. Margrey, Amy D. Hazzard, and Jonathan R. Scheerer*
Department of Chemistry, The College of William & Mary, P.O. Box 8795, Williamsburg, Virginia 23187, United States
S
* Supporting Information
ABSTRACT: A general strategy for the conversion of [2.2.2]-diazabicyclic alkene structures to 2-pyridone aromatic heterocyclic
products is reported. The reaction sequence starts from 2,5-diketopiperazine (DKP) derivatives, is compatible with both aromatic
and aliphatic aldehyde components, and can intercept either intra- or intermolecular cycloaddition manifolds. Priming of one aza-
bridging function in the intermediate [2.2.2]-DKP scaffold permits cycloreversion (microwave heating) and selective extrusion of
cyanate derivatives leading to the formation of 2-pyridone structures. Progress toward the synthesis of louisianin A and B,
antiproliferative 2-pyridone natural products, is also disclosed.
demonstrated the first Diels−Alder cycloaddition of a
pyrazinone, also noted the thermal decomposition of a
[2.2.2]-diazabicyclic alkene cycloadduct (Figure 1).14a On
2-Pyridones are a valuable and widespread class of aromatic
heterocycles. The 2-pyridone scaffold is observed within natural
products, pharmaceutical reagents and agrochemicals, and has
found applications in polymer1 and materials chemistry as well
as fluorescence imaging.2 Several biologically active molecules
containing this moiety are widely used in the clinic (such as the
antitumor agent camptothecin3 and semisynthetic analogues)
or are important lead compounds in the development of new
medicinal agents that target cancer, MRSA and VRE bacterial
infections, HIV-1, autoimmune disorders, and cognitive
decline.4
Several means exist for the synthesis of pyridones, but new
methods for the preparation (and derivation5) of 2-pyridones
and 2-alkoxypyridines are relevant and of current interest.4,6
Although traditional condensation methodologies remain a
powerful tool, recently developed strategies centered on metal-
catalyzed annulation,7 olefin metathesis,8 and novel cyclization
chemistry9 increase the diversity of substituted pyridine and
pyridone derivatives that are synthetically accessible. Merged
cycloaddition−cycloreversion strategies are known for the
synthesis of a number of aromatic heterocycles,10 although
such strategies have been exploited in a limited sense for the
synthesis of 2-pyridones.11 In particular, 5-alkoxy-1,2,4-
triazines12 or 5-silyloxy-1,4-oxazinones13 will undergo [4 +
2]/retro-[4 + 2] with suitable (electron-rich) dieneophiles.
2-Pyrazinones offer expanded scope and improved reactivity
with regard to cycloaddition and readily undergo Diels−Alder
reaction with both electron-rich or -deficient dieneophilic
substrates at reasonable temperatures, in many cases at or near
ambient temperatures.14,16a When pyrazinone cycloaddition
occurs with alkyne substrates, the resulting [2.2.2]-diazabicyclic
adducts can undergo cycloreversion to give 2-pyridones. The
original 1970 communication by Porter and Sammes, which
Figure 1. (1,2) Precedent r[4 + 2] of [2.2.2]-diazabicycloalkene to 2-
pyridone products; (3) thermally stable [2.2.2]-DKP structures.
heating, the diketopiperazine (DKP) cycloadduct 2 underwent
cycloreversion and extrusion of isocyanic acid to provide 2-
pyridone 3 (yield not given). Other examples of this chemistry
are encompassed by adducts derived from cycloaddition of 3,5-
dichloro-2(1H)-pyrazinone (4) (and related derivatives there-
of).15 The aza-bridging functionalities in the intermediate
[2.2.2]-cycloadducts derived from 3,5-dichloro-2-pyrazinone
Received: December 18, 2013
Published: January 29, 2014
© 2014 American Chemical Society
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Letter
substrates are not identical, and cycloreversion affords mixtures
of 2-pyridone and pyridine products (5 or 6). The predictive
capacity of which competing cycloreversion will dominate is
limiting, and separation of the mixture of products is not
possible in some cases.15 Because retrograde Diels−Alder
reactions that extrude cyanate and cyanogen derivatives are not
well understood in comparison to other 2π components10 (e.g.,
N2, CO2), investigation in this area might provide new insights
and increase the synthetic utility of this reaction.
We recently developed a “one-pot” domino reaction
sequence comprising an aldol condensation, alkene isomer-
ization, and Diels−Alder cycloaddition for the asymmetric
construction of [2.2.2]-diazabicyclic alkaloid structures. In these
studies, we employed mostly alkene substrates, but several
alkyne dieneophiles were used leading to bicyclo-DKP alkene
products (e.g., 7−9).16 Neither the lactim O-methyl ether in 7
or 9 nor the primary or secondary lactam in 8 showed proclivity
toward retrograde Diels−Alder reaction; all were thermally
stable.
We were curious about the divergent reactivity and threshold
for cycloreversion with the Sammes example (eq 1) and with
substrates prepared in our lab (eq 3). We set out to explore
these differences and targeted two goals: (1) improve the scope
and generality of the domino reaction sequence for the
construction of [2.2.2]-diazabicyclic DKP structures and (2)
determine general conditions for cycloreversion that selectively
afford 2-pyridone products. While the DKP products (7−9)
bearing the chiral aminal are effective for controlling diastereo-
facial selectivity in the cycloaddition event, these nonracemic
substrates were unnecessary for a methodological study given
the achiral nature of the desired 2-pyridone products.
Accordingly, we selected two DKP substrates to begin our
exploration, the glycine- and proline-derived DKPs 12 and 13
(Scheme 1). The dimethoxybenzyl (DMB)-protected DKP 12
1.2 equiv). Following exposure to DBU (1.5 equiv), elimination
to exocyclic diene 16 and isomerization to 17 was observed and
Diels−Alder cycloaddition ensuded, delivering [2.2.2]-DKP
adduct 18 in 46% isolated yield. Cycloadduct 18 was thermally
stable up to 200 °C.19 Given the low threshold for extrusion of
isocyanate in the Sammes precedent (Figure 1, eq 1), we
converted the lactim O-methyl ether in 18 to the lactam in 19
(KI, AcOH, 100 °C) in hopes of rendering the cycloreversion
more favorable. The resulting DKP 19 was also unreactive
toward thermolysis (up to 200 °C).
We then modified the electronic nature of the aza-bridging
function in 19 by converting the lactam into the derived lactim
carbonate 20. Thermolysis of 20 (microwave heating, 300 W, 1
h) afforded both the desired cycloreversion product, pyridone
22, and returned lactam 19. The presence of lactam 19 as a
product indicates that thermal decomposition of the Boc
residue is competitive with cycloreversion and extrusion of
cyanogen carbonate. Activation of the lactam 19 as the lactim
acetate 21 (Ac2O, pyr) permitted cycloreversion under identical
thermolysis conditions but afforded a single observed product,
pyridone 22 (84% isolated yield from 19). In this study,
microwave heating emerged as an operationally convenient tool
to access elevated temperatures above 150 °C, preserve short
reaction durations (1 h), and permit the use of toluene as a
reaction solvent (thereby facilitating evaporation following
completion of the reaction).
The synthetic sequence leading to pyridones can also be
accomplished starting with DKP 13 and benzaldehyde 14b,
which bears aryl substitution at the alkyne terminus (Figure 2).
We noted that during thermolysis of the intermediate lactim
acetate derived from 24 there was no notable change in the
cycloreversion threshold, suggesting that nonbonding inter-
actions do not appreciably accelerate the extrusion of cyanate
and formation of pyridone 25.
The one-pot aldol condensation, alkene isomerization, and
Diels−Alder cycloaddition sequence was also completed using
the DMB-protected DKP 12 with both 14a and 14b.
Conversion of corresponding cycloadducts 26a and 26b into
pyridones 28a and 28b proceeded in analogous fashion. The
DMB protecting group was retained through the series of
reactions leading toward pyridones and proved stable to both
demethylation (KI, AcOH, 100 °C) and thermolysis. After
becoming inured to frequent use of the microwave, and in
order to demonstrate the utility of the DMB as a protecting
group for 2-pyridones, we removed the functionality on 28b
with anhydrous acid (TFA in CH2Cl2) at 120 °C (15 min,
microwave) to reveal the unprotected tricyclic pyridone 29
(78% yield).
Scheme 1. Synthesis of DKP Lactim O-Methyl Ether
Substrates
In the reactions described thus far, the intermediate [2.2.2]-
cycloadducts were prepared by intramolecular Diels−Alder
cycloaddition. Intermolecular cycloaddition is also possible but
requires slightly modified reaction conditions in order to
employ electron-deficient dieneophiles such as dimethyl-
acetylene dicarboxylate (DMAD) (Scheme 3). Toward this
end, aldol condensation and alkene isomerization by the usual
method (using 13 and benzaldehyde) afforded the intermediate
azadiene [4 + 2] precursor 30. Aqueous workup was required
to eliminate residual DBU base (in order to prevent Michael
additions) prior to the introduction of DMAD and submission
to the Diels−Alder reaction conditions (warming to 60 °C). In
this way, the desired [2.2.2]-diazabicyclic cycloadduct 31 could
be prepared in 82% yield from 13.20
can be prepared in four operations (55% overall yield). The
synthesis of 13 proceeds in analogous fashion (3 steps, 80%
yield) from proline methyl ester.17
We initiated our study with DKP 13 and 2-ethynyl-
benzaldehyde (14a). Although sodium methoxide is an effective
reagent to carry out aldol condensation and alkene isomer-
ization on 13, the ethynyl benzaldehyde 14a was not stable and
rapidly cyclized to the enol acetal 15 (Scheme 2).18 By using a
non-nucleophilic amide base (LiHMDS) and sequential
addition of reagents, the desired reaction sequence could be
accomplished. To this end, enolization of the DKP substrate
followed by aldol addition into 2-ethynylbenzaldehyde (14a)
preceded acylation of the intermediate β-alkoxy adduct (Ac2O,
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Scheme 2. Formation of 2-Pyridone from [2.2.2]-Diazabicyclic Intermediate by Selective Extrusion of Activated Cyanic Acid
cycloreversion and ejection of the alternate aza bridge
(extruded as the tethered isocyanate) to give the observed
methoxy pyridine 32 (75% yield).
At this point in the study, we demonstrated a general
sequence that can provide 2-pyridones from DKP and aromatic
aldehyde components via an intermediate [2.2.2]-diazabicyclo-
alkene cycloadduct. We wanted to also determine if the
sequence was viable with aliphatic aldehydes, and we selected
louisianin A (39) and B (40) as as instructive models to
validate this chemistry. The louisianin alkaloids possess
antitumor activity and were isolated in 1995 from cultured
Streptomyces sp. WK-4028 found in a Louisiana soil sample.21
Four distinct strategies toward the louisianin alkaloids have
appeared,22 and two syntheses of 39 are reported.23
Our route began with the union of DKP 12 and acetylenic
aldehyde 35 using the one-pot reaction sequence to deliver
cycloadduct 36 in 82% yield (Scheme 4). The [2.2.2]-
Scheme 4. Synthesis of Louisianin Alkaloids A and B
Figure 2. Synthesis of 2-pyridone alkaloids. Standard conditions: (a)
(i) LiHMDS, −78 °C; 14a or 14b; (ii) Ac2O, −78 to 23 °C; (iii)
DBU, 23 to 100 °C. (b) KI, AcOH, 100 °C. (c) Ac2O, pyr, 100 °C. (d)
Microwave, 300 W, power mode, 1 h.
Scheme 3. Selective Preparation of 2-Pyridone or
Regioisomeric 2-Methoxy Pyridine
diazabicycle 36 proved thermally stable up to 200 °C; however,
modulating the electronic nature of the lactim bridge again
improved the propensity for cycloreversion. Conversion of the
lactim O-methyl ether in 36 into the lactim acetate enabled
cycloreversion at reasonable temperatures and duration (300
W, 1 h) and afforded pyridone 38 in 82% yield from 36 (3
steps). Pyridone 38 contains the core structure of louisianin A
and B (39, 40); oxidation and DMB deprotection remain to
complete the synthesis of these natural products.
With cycloadduct 31 in hand, we were able to reveal some
interesting cycloreversion reactivity. While the standard
protocol comprising demethylation, activation, and thermolysis
was able to deliver pyridone 34 without event, direct exposure
of 31 to thermolysis conditions (300 W, 1 h), promoted the
In conclusion, we have demonstrated a general method for
the synthesis of 2-pyridones by cycloreversion of [2.2.2]-
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diazabicycloalkene DKP intermediates. Reliable cycloreversion
can be accomplished by activation of one aza-bridging
functionality as the derived lactim acetate. The synthetic
sequence highlights a valuable synthetic route toward 2-
pyridones and demonstrates rapid assembly of polycyclic
architectures from simple starting materials.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jrscheerer@wm.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Donors of the ACS Petroleum
Research Fund.
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