Facile Synthesis of Spirocyclic Lactams via [3+2] and [3+3] Aza-Annulation Reactions

Article abstract of DOI:10.1002/ejoc.202100255

Spirocyclic pyrrolidones and piperidones were synthesized starting from readily available α-ketolactones and α-ketolactams employing [3+2]- and [3+3]-aza-annulation reactions. Annulation reactions proceeded with good yields and further reduction of the ex

Full text of DOI:10.1002/ejoc.202100255

Communications
doi.org/10.1002/ejoc.202100255
Facile Synthesis of Spirocyclic Lactams via [3+2] and
[3+3] Aza-Annulation Reactions
Davit Hayrapetyan*[a] and Valeriya Stepanova[a]
Spirocyclic pyrrolidones and piperidones were synthesized
starting from readily available α-ketolactones and α-ketolac-
tams employing [3+2]- and [3+3]-aza-annulation reactions.
Annulation reactions proceeded with good yields and further
reduction of the exocyclic C=C double bond of the enamide
moiety proceeded with excellent diastereoselectivity. Overall,
one CÀ C and two CÀ N bonds, as well as three new stereo-
centers were created in a diastereoselective manner resulting in
a fast upbuild of molecular complexity.
Introduction
Spirocyclic N-heterocycles are privileged building blocks in drug
discovery because of their 3D character[1,2] (escaping from
aromatic flatland), conformational restriction, improved phys-
icochemical properties, compared to their monocyclic analogs,
and improved metabolic resistance (Scheme 1a).[3–8]
Common methodologies for assembling spirocyclic scaffolds
are mainly relaying on intramolecular SN2 alkylation[9–19] and N-
acylation,[11,20,21] ring closing metathesis[20,22–24] of the appropriate
precursors. Additionally, metal-catalyzed[25–28] and hypervalent
iodine
mediated[29]
dearmoatization
reactions,
Prins
reaction[30–32] and cycloaddition reactions[23,33–35] should be
mentioned.
Recently several appealing approaches have been reported
for de-novo assembly of the aza-spirocycles. Bode suggested a
spirocyclization strategy relying on SnAP cyclization
reaction.[36,37] Despite its chemical elegance it suffers from the
waste intensiveness and high toxicity of the used precursors,
reagents, and produced waste (tributyltin compounds). Mykhai-
liuk from Enamine Ltd. proposed a spirocyclization method
based on [3+2]-cycloaddition reaction between electron-
deficient alkenes and in situ generated highly reactive azome-
thine ylide.[38,39] However, the lack of stereocontrol during the
key cycloaddition step is the main weakness of this strategy.
Recently Mykhailiuk reported a unified spirolactam synthesis
from α-aminoesters, relying on Dieckmann condensation
(Scheme 1b).[40] Gaunt reported a visible-light-mediated syn-
thesis of aza-sprirocycles using photocatalytic single electron
transfer (SET) reduction of iminium intermediate-radical cycliza-
Scheme 1. Aza-spirocyclic motifs in drugs and recent works in the synthesis
of N-spirocyclic building blocks. Herein we would like to disclose a divergent
synthesis of 5,5- and 5,6-spirocyclic lactams based on the aza-annulation
reaction (Scheme 1c).
tion sequence.[41] Bode employed catalytic hydrogen atom
transfer reduction of electron-rich olefins with a generation of
C-centered radicals in the presence of imines for the intra-
molecular radical cyclization with the formation of spirocyclic
morpholines.[42] Recently Krasavin group reported several
[a] Dr. D. Hayrapetyan, V. Stepanova
Department of Chemistry, School of Sciences and Humanities,
Nazarbayev University
53 Kabanbay Batyr Ave., 010000 Nur-Sultan, Kazakhstan
spirocyclization
procedures
based
on
α-diazolactam
chemistry.[43,44]
E-mail: davit.hayrapetyan@nu.edu.kz
To the best of our knowledge, [3+2] and [3+3]-aza-
annulation reactions between enamines and maleic and
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100255
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itaconic anhydrides,[45–48] were not employed for the construc-
reaction mixture from 3d and maleic anhydride was reduced
directly in a one-pot procedure to provide spirocycle 5d, which
was purified using column chromatography without any
complications. Interaction of bulky enamines 3e–g with maleic
anhydride proceeded smoothly and afforded desired spirolac-
tams 4e–g with good yields (73–75%) as single diastereomers.
Interestingly, the substitution of terminal hydrogens of the
exocyclic enamide C=C double bond with alkyl groups resulted
in complete suppression of its reactivity in the reduction with
borohydride reagents under acidic conditions. Cyclization of
enamine 3h with maleic anhydride resulted in a mixture of E/Z
isomers (95:5) of the monosubstituted exocyclic double bond,
as expected. Reduction of the obtained mixture of isomers
under standard conditions was somehow sluggish and pro-
longed reaction times were required to achieve full conversion
and afford spirolactam 5h as a single diastereomer. Finally, the
interaction of enamine 3i, bearing bulky isopropylamine
moiety, with maleic anhydride resulted in a complicated
reaction mixture.
Next, we investigated [3+3] aza-annulation reaction enam-
ines 3a–i with itaconic anhydride which would result in a
formation of spirocyclic piperidones (Scheme 2d). Thus, in the
case of enamines 3a–b cyclization proceeded with excellent
selectivity, affording the desired spiropiperidones 6a–b as
single diastereomers. The reduction of the enamide double
bond with borohydride reagents, such as NaBH4 and NaBH3CN
in acetic acid proceeded with good yields (54–56%) and
excellent selectivity. In the case of interaction of 3d with
itaconic anhydride, the non-chromatographic isolation of the
cyclization product was not viable and the desired spirocycle
7d was purified by standard column chromatography after the
one-pot aza-annulation/reduction sequence. The cyclization of
itaconic anhydride with bulky enamines 3e–f proceeded
smoothly and afforded spiropiperidones 6e–f with good yields
(56–58%) as single diastereomers. However, in contrast to
[3+2]-annulation, aza-annulation with enamine 3g failed and
its interaction with itaconic anhydride resulted in a complex
mixture. Analogously to 4e–g, enamides 6e–f turned to be
stable in the acidic media and they remained untouched under
reductive conditions (NaBH3CN or NaBH4/AcOH). Not surpris-
ingly, enamine 3h afforded a mixture of E/Z isomers, upon
treatment with itaconic anhydride and the attempted reduction
of the reaction mixture with NaBH4 in AcOH was sluggish and
never went to completion. Finally, while the cyclization of bulky
enamine 3i with maleic anhydride failed, its interaction with
itaconic anhydride resulted in spirocycle 6i with 79% yield as a
single diastereomer. The increased bulkiness of the N-substitu-
ent in 6i did not have any noticeable effect in the reduction of
the enamide moiety and the product 7i was obtained in 78%
yield as a single diastereomer.
tion of spirocycles up to date, whereas such reactions would be
advantageous from the standpoints of stereochemical control
and prospects of post-synthetic modifications of the newly
formed building blocks.
Results and Discussion
In our synthetic studies, we relied on readily available starting
materials. Thus, α-ketolactams (2c–i, see supporting informa-
tion) were prepared by Dieckmann-type condensation of
lactams (1) with appropriate esters in refluxing toluene, using
NaH as the base[49] (Scheme 2a). Despite moderate yields (26–
44%) of such reactions, their practical applicability is justified
by the availability of starting materials and the practicability of
purification of the α-ketolactams via their Na-salts, thus
avoiding column chromatography. Alternatively, the desired
ketolactams can be prepared by deprotonation of lactams with
LDA at low temperatures and quenching the Li-enolates with
appropriate esters,[50] however in the latter case the yields were
comparable with the NaH method (see supporting information
for the details). Condensation between α-ketolactams as well as
α-acetylbutyrolactone with primary amines proceeded readily
in refluxing chloroform while using 4 Å molecular sieves as the
dehydrating agent (3a,c,d,h,i). However, in the case of bulky
ketones (3e–g) and less nucleophilic amines (3b) full con-
version was achieved after one week of reaction time
(Scheme 2a, Scheme 2b).
As an entry into spirocyclic lactams, we chose the
interaction of enamines 3a–i with maleic anhydride (Sche-
me 2a, Scheme 2c). To our delight, the cyclization between
maleic anhydride and enamine 3a proceeded with excellent
selectivity and afforded spirolactam 4a with 88% yield as a
single diastereomer. To underline the practical utility of the
reaction, we performed a scale-up experiment, which afforded
13.04 g (87%) of 4a straightforwardly, without the need for
chromatographic purification. Not surprisingly, the exocyclic
enamide double bond in the resulting molecule 4a turned to
be unstable under acidic conditions, such as chromatography
on silica gel with an acidic eluent (CHCl3/MeOH/AcOH) and
Fisher esterification (MeOH, H2SO4). Reduction of enamide 4a
with both NaBH3CN and NaBH4 in acetic acid proceeded
diastereoselectively providing reduced spirocycle 5a with good
yields (60–80%). The scale-up reduction with NaBH4 in acetic
acid provided 8.53 g (80%) of 5a. Whereas in most cases the
annulation products could be obtained directly in a decently
pure form via precipitation or trituration with appropriate
solvents, in several cases additional purification was required.
Because of the sensitivity of the exocyclic enamide moiety to
the acidic chromatography conditions (silica gel, eluent with
5% acetic acid) a short workaround was required in order to
obtain analytically pure compounds. Thus, esterification of
carboxylate function with CH3I/K2CO3 followed by chromato-
graphic purification of the ester, reduction with NaBH3CN, and
hydrolysis of the methyl ester was performed for 5b and 5c
(see supporting information). As an alternative procedure, the
The rationalization of the observed diastereoselectivity of
cyclization reactions is shown in Scheme 2e.[46] First, the
conjugate addition of maleic and itaconic anhydrides results in
intermediates B and E, respectively, where the imine moiety is
located in close proximity to the anhydride group. Next,
anhydride opening (intermediates C and F) and proton transfer
steps would provide the final spirocycles 4 and 6 with the given
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Scheme 2. Synthesis of the spirocyclic lactams, scope of the method, and rationalization of the observed diastereoselectivity.
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Keywords: Annulation
·
Diastereoselectivity
·
Lactams
·
Nitrogen heterocycles · Spiro compounds
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Conflict of Interest
The authors declare no conflict of interest.
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