Synthesis of Enantioenriched gem-Disubstituted 4-Imidazolidinones by Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

Article abstract of DOI:10.1021/acs.orglett.1c02134

A variety of enantioenriched gem-disubstituted 4-imidazolidinones were prepared in up to >99% yield and 95% ee by the Pd-catalyzed decarboxylative asymmetric allylic alkylation of imidazolidinone-derived β-amidoesters. In the process of preparing these substrates, a rapid synthetic route to 4-imidazolidinone derivatives was developed, beginning from 2-thiohydantoin. The orthogonality of the benzoyl imide and tert-butyl carbamate groups used to protect these nitrogen-rich products was demonstrated, enabling potential applications in drug design.

Full text of DOI:10.1021/acs.orglett.1c02134

pubs.acs.org/OrgLett
Letter
Synthesis of Enantioenriched gem-Disubstituted 4‑Imidazolidinones
by Palladium-Catalyzed Decarboxylative Asymmetric Allylic
Alkylation
Zachary P. Sercel, Alexander W. Sun, and Brian M. Stoltz*
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ABSTRACT: A variety of enantioenriched gem-disubstituted 4-imidazolidinones were prepared in up to >99% yield and 95% ee by
the Pd-catalyzed decarboxylative asymmetric allylic alkylation of imidazolidinone-derived β-amidoesters. In the process of preparing
these substrates, a rapid synthetic route to 4-imidazolidinone derivatives was developed, beginning from 2-thiohydantoin. The
orthogonality of the benzoyl imide and tert-butyl carbamate groups used to protect these nitrogen-rich products was demonstrated,
enabling potential applications in drug design.
early 75% of small-molecule drugs contain at least one
(Scheme 1b). We report our efforts to extend this method-
ology to the 5-membered imidazolidinone substrate class,
enabling rapid access to stereochemically complex imidazoli-
dinones suitable for further functionalization (Scheme 1c).
We began by developing a rapid and scalable synthetic route
to imidazolidinone allylic alkylation substrates 7, which proved
to be a considerable challenge. We anticipated that the use of a
Boc protecting group at the 4-position would be essential for
high enantioselectivity by analogy to other substrate classes.6b
Several routes to unsubstituted or carbamate-protected 4-
imidazolidinones have been reported, but none of these routes
were conducive to reliable material throughput in our hands.7
Nevertheless, we were able to develop a rapid synthesis of 7
from 2-thiohydantoin (1) (Scheme 2).
2-Thiohydantoin (1) was subjected to precedented Boc
protection to provide carbamate 2,8 followed by nickel boride
mediated reductive desulfurization to produce Boc-protected
4-imidazolidinone 3 in high yield.9,10 Subsequent benzoylation
furnished doubly protected imidazolidinone derivative 4.
Acylation of 4 proved challenging due to the extremely rapid
reactivity of the corresponding enolate toward starting material
even at −108 °C, but the use of acylimidazole electrophile 511
and the precombination of 5 with LiHMDS prior to starting
1
Nnitrogen heterocycle.
However, despite a significant
correlation between the Csp3 complexity of a drug and its
clinical success,2 most of the heterocycles found in marketed
drugs lack stereochemical complexity. This phenomenon can
largely be attributed to a lack of synthetic methods for the
efficient incorporation of chiral centers into medicinally
relevant heterocycles.
4-Imidazolidinones are a class of nitrogen-rich saturated
lactams that have found applications in medicinal chemistry
(Scheme 1a). Our attention was drawn to the fully substituted
(albeit achiral) tertiary carbon atom at the 5-position of several
of the drugs and drug candidates bearing this heterocyclic
moiety, such as the spirocyclic drug spiperone. Given the
prevalence of this substitution pattern, we reasoned that drug
design would potentially benefit from a methodology for the
asymmetric construction of chiral 4-imidazolidinones bearing
fully substituted tertiary stereocenters. 4-Imidazolidinones have
also been used as chiral auxiliaries in the preparation of
artificial amino acids3 and have found applications in popular
organic catalysts,4 but to our knowledge, preparation of these
species has been largely restricted to processes involving the
use of chiral pool materials or kinetic resolution.
Our group and others have reported extensively on the
palladium-catalyzed decarboxylative asymmetric allylic alkyla-
tion reaction,5 including several recent publications detailing
the use of these methods for the preparation of 6- and 7-
membered gem-disubstituted diazaheterocycles.6 gem-Disubsti-
tuted tetrahydropyrimidin-4-ones, piperazin-2-ones,6b and 1,4-
diazepan-5-ones6c are all available in high yield and
enantioselectivity via our group’s allylic alkylation chemistry
Received: June 25, 2021
https://doi.org/10.1021/acs.orglett.1c02134
© XXXX American Chemical Society
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A

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Letter
a
Scheme 1. gem-Disubstituted Diazaheterocycles by Pd-
Table 1. Solvent Screen
Catalyzed Decarboxylative Asymmetric Allylic Alkylation
b
entry
solvent
ee (%)
c
1
2
3
4
5
THF
51
68
89
87
91
1,4-dioxane
benzene
PhMe
2:1 hexanes/PhMe
a
Screening was performed on a 0.01 mmol scale at 0.014 M
concentration. Reactions proceeded to completion unless otherwise
b
noted. For additional experimentation, see the SI. Values determined
c
by chiral SFC analysis. Reaction incomplete after 45 h.
a
Scheme 3. Substrate Scope
Scheme 2. Synthesis of Allylic Alkylation Substrates 7
material addition allowed desired 1,3-dicarbonyl 6 to be
prepared in 50% yield on a multigram scale. To our delight,
treatment of 6 with base and various electrophiles allowed for
the rapid preparation of multiple allylic alkylation substrates
7.12
a
Reactions were performed on a 0.1 mmol scale at 0.014 M
concentration. ee values were determined by chiral SFC analysis.
b
c
Conducted at 40 °C. 1.86 mmol scale: 86% yield, 95% ee.
d
Pd2(dba)3 was used instead of Pd2(pmdba)3 to facilitate product
With model substrate 7a in hand, beginning with the
conditions for our group’s prior allylic alkylation of N-Boc
piperazinones,6b a brief solvent screen was conducted for the
optimization of enantioselectivity (Table 1). In line with
previously observed trends, ethereal solvents provided the
product 8a in only modest enantioselectivity. Less polar
solvents such as benzene and toluene resulted in promising
levels of enantioselectivity, but the use of a nonpolar hexanes/
toluene mixture led to an ee of 91%.
Using this optimized solvent system, we examined the
palladium-catalyzed decarboxylative asymmetric allylic alkyla-
tion of 4-imidazolidinone substrates 7a−k (Scheme 3).
Various nonpolar side chains proved to be well-tolerated,
purification.
such as benzyl (8a), p-trifluoromethylbenzyl (8b), methyl
(8c), prenyl (8d), and cinnamyl (8e) groups. A propargyl
group was also tolerated with high enantioselectivity (8f),
albeit with a reduction in yield. We were pleased to observe
that the reaction proceeded smoothly with a methyl group at
the 2-position of the allyl fragment (8g). Lastly, several polar
functional groups were also well-tolerated in the allylic
alkylation (8h−k), including an alkenyl chloride and a
carbamate. In particular, nitrile substrate 8j was obtained in
quantitative yield and an excellent 95% ee.
B
https://doi.org/10.1021/acs.orglett.1c02134
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Having demonstrated the broad functional group tolerance
of the reported method, we sought to explore the feasibility of
further functionalization of the 4-imidazolidinone products
(Scheme 4). The selective removal of either protecting group
would likely prove essential for applications in medicinal
chemistry. Toward this end, treatment of chiral benzyl
imidazolidinone 8a with TFA led to facile Boc cleavage,
affording free secondary amine 9. Similarly, treatment of 8a
with lithium hydroxide readily affected benzoyl group removal,
providing free lactam 10.
Experimental procedures, characterization data for all
new compounds, and NMR and IR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Brian M. Stoltz − Warren and Katharine Schlinger
Laboratory of Chemistry and Chemical Engineering, Division
of Chemistry and Chemical Engineering, California Institute
of Technology, Pasadena, California 91125, United States;
orcid.org/0000-0001-9837-1528; Email: stoltz@
caltech.edu
Scheme 4. Product Transformations
Authors
Zachary P. Sercel − Warren and Katharine Schlinger
Laboratory of Chemistry and Chemical Engineering, Division
of Chemistry and Chemical Engineering, California Institute
of Technology, Pasadena, California 91125, United States
Alexander W. Sun − Warren and Katharine Schlinger
Laboratory of Chemistry and Chemical Engineering, Division
of Chemistry and Chemical Engineering, California Institute
of Technology, Pasadena, California 91125, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02134
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The NIH-NIGMS (R01GM080269) and Caltech are thanked
for financial support. Z.P.S. thanks the Rose Hills Foundation
for support via a Rose Hills Foundation Graduate Fellowship
and the National Science Foundation for a predoctoral
fellowship. A.W.S. thanks the NIH-NIGMS for a predoctoral
fellowship (Ruth L. Kirschstein Institutional National Research
Service Award F30GM120836) and a UCLA-Caltech Medical
Scientist Training Program Fellowship (T32GM008042). We
thank Dr. Scott Virgil (Caltech) for instrumentation and
helpful discussions, Dr. David VanderVelde (Caltech) for
NMR expertise, and Dr. Mona Shahgoli (Caltech) for mass
spectrometry assistance.
At the outset of this research, we had planned to explore the
conversion of 4-imidazolidinone allylic alkylation products 8a−
k to synthetically useful derivatives of biologically relevant and
synthetically challenging α,α-disubstituted α-amino acids.13
Imidazolidinones were envisioned as surrogates for these
desirable compounds based on prior examples of imidazolidi-
none chiral auxiliary-based strategies to access α,α-disubsti-
tuted α-amino acids,3 as well as our own group’s preparation of
quaternary substituted β-amino acids from the analogous
tetrahydropyrimidinones.6b Unfortunately, the presence of
olefinic functionality hampered the feasibility of converting
8a−k into amino acid derivatives due to the harsh conditions
required for ring opening. Despite extensive experimentation,
the highest yielding conditions identified for the conversion of
imidazolidinone 8a to amino ester 11 (H2SO4/MeOH)
provided highly variable results, with the maximum observed
yield of 11 being only 25%.
This research represents the first direct catalytic asymmetric
synthesis of gem-disubstituted 4-imidazolidinones. Applying
palladium-catalyzed decarboxylative asymmetric allylic alkyla-
tion to this nitrogen-rich substrate class enabled access to
enantioenriched imidazolidinones bearing diverse functional
groups in high yield and enantioselectivity. This methodology,
in combination with the demonstrated orthogonality of the
protecting groups of the products, could enable access to a
novel class of medicinally relevant compounds.
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ASSOCIATED CONTENT
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