Scaffolding-Induced Property Modulation of Chemical Space

Article abstract of DOI:10.1021/acscombsci.0c00072

Physicochemical property switching of chemical space is of great importance for optimization of compounds, for example, for biological activity. Cyclization is a key method to control 3D and other properties. A two-step approach, which involves a multicomponent reaction followed by cyclization, is reported to achieve the transition from basic moieties to charge neutral cyclic derivatives. A series of multisubstituted oxazolidinones, oxazinanones, and oxazepanones as well as their thio and sulfur derivatives are synthesized from readily available building blocks with mild conditions and high yields. Like a few other methods, MCR and cyclization allow for the collective transformation of a large chemical space into a related one with different properties.

Full text of DOI:10.1021/acscombsci.0c00072

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Article
Scaffolding-induced property modulation of chemical space
Jingyao Li, Vincenzo Di Lorenzo, Pravin Patil, Angel J. Ruiz Moreno, Katarzyna Kurpiewska,
Justyna Kalinowska-T#u#cik, Marco A. Velasco-Velázquez, and Alexander Dömling
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.0c00072 • Publication Date (Web): 22 May 2020
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Scaffolding-induced property modulation of chemical space
Jingyao Li,† Vincenzo Di Lorenzo,§,† Pravin Patil,† Angel J. Ruiz Moreno∥,†, Katarzyna Kurpiewska‡,
Justyna Kalinowska-Tłuścik‡, Marco A. Velasco Velázquez∥ and Alexander Dömling†*
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† University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
§ Università degli studi di Napoli Federico II, Department of Pharmacy, Via Domenico Montesano 49, 80131 Napoli, Italy
∥ Universidad Nacional Autónoma de México, Departamento de Farmacología, Unidad Periférica de Investigación en Biomedicina
Traslacional, Facultad de Medicina y Programa de Doctorado en Ciencias Biomédicas, C.P. 04510, Ciudad de México, México.
‡ Jagiellonian University, Faculty of Chemistry, Gronostajowa 2, 30-387 Krakow, Poland
*e-mail: a.s.s.domling@rug.nl, www.drugdesign.nl
Supporting Information Placeholder
ABSTRACT: Physicochemical property switching of chemical space is of great importance for optimization of compounds, for
example for biological activity. Cyclization is a key method to control 3D and other properties. A two-step approach, which
involves a multicomponent reaction followed by cyclization, is reported to achieve the transition from basic moieties to charge
neutral cyclic derivatives. A series of multi-
O
H
N N
substituted
oxazolidinones,
oxazinanones,
1. Ugi-tetrazole
2. Cyclization
O
CN R2
N
N
1. GBB reaction
2. Cyclization
N
R2
R1
+
oxazepanones as well as their thio- and sulfur-
derivatives are synthesized from readily available
building blocks with mild conditions and high
yields. Like few other methods, MCR and
cyclization, MCR and cyclization allow for the
S
S
R1
N
R1'
R1
O
N
X
N
X =
N
R2
X
OH
H
O
O
O
5 examples
up to 70% yield
Multi-substitued • Multi-heterocyclic consititution
Easily operate • Mild condition
19 examples
up to 80% yield
Excellent scalability and efficiency
collective transformation of a large chemical space into a related one with different properties.
KEYWORDS: multicomponent reaction, cyclic carbamate, Ugi reaction, cyclization, tetrazole, scaffolds diversity
■ INTRODUCTION
A: 3D structure comparision of cyclic and non-cyclic compounds
The property design of organic compounds is of uttermost
importance during the process of optimization to obtain
compounds with perfect performance. Properties such as
charges or neutrality, 3D distribution of lipophilic or hydrogen
donor/acceptor moieties are introduced into molecules by an
often lengthy, stepwise and sequential pathway. The principles
of multicomponent reaction chemistry (MCR) allow for an
orthogonally different approach.1 In an intellectually and
operationally easily building block approach, complex
molecules are assembled in one-step from a very large number
of available building blocks.2,3,4,5 Amongst, derivatization
which often changes the properties dramatically are
cyclizations. In the context of medicinal chemistry, cyclizations
are often introduced to rigidify and generate a conformation
similar to the receptor-bound structure, and also to modify drug-
like properties such as stability to metabolism or increasing
permeability.6 By overlapping the 3D structure of cyclic and
non-cyclic compounds, stabilization via cyclization and a shift
of the terminal moiety was observed (Figure 1A). While the
number of primary MCRs with useful synthetic properties such
as great scope, ease of performance and large number of
building blocks (and thus chemical space) is limited, the
number of secondary transformations and especially
cyclizations is shire infinitely. Hulme and others introduced the
very useful concept of UDC (Ugi-deprotection-cyclization)
resulting in Epelsiban and Retosiban, which are currently tested
in advanced clinical trials.7,8
N
N
N
N
N
N
N
N
N
N
H
OH
O
O
B: Representitive Drugs containing a cyclic carbamate moiety
F3
C
O
N
O
H
N
Cl
Cl
O
O
H
Cl
O
N
N
O
S
N
O
O
H
O
Parafon
(muscle spasms/pain)
Sustiva
(infectious diseases)
Xarelto
(Cardiovascular Diseases)
C: Privious synthetic approaches to cyclic carbamates
Halogen
Cl
NCO
Process:
O
water sensitive
metallorganic
poisonous
expensive
limited diversity
R1
N
H
OH
R1
Halogen
O
N
Cbz
N
R
N
H
Ar
OH
D: MCR/cyclization sequence (our work)
N
N
N
O
N
R2
operationally simple
not sensitive
general
Ugi-tetrazole
H
1.
R1
S
S
N
X
O
CN R2
Cyclization
2.
X =
+
O
cheap
R1'
R
1 1.
2.
O
O
GBB
reac
Cyclization
N
large chemical space
OH
N
H
R1
ti
on
N
O
N
X
R2
Figure 1. Cyclization strategies in chemistry.
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Carbamate containing heterocycles are abundantly present as
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corresponding Ugi-tetrazole in hand, the optimization started
with 1 equivalent of CDI in DCM at room temperature, giving
a moderate yield of 76% (Table 1, entry 1) after 3 h. Further
optimization was conducted by increasing either temperature or
the equivalent of CDI. As expected, both conditions performed
better yields of 83% (Table 1, entry 2) and 93% (Table 1,
entry 3), respectively. Several researches indicated that a
catalytic amount of base in CDI reaction will accelerate the
formation of the corresponding product.29 However, subsequent
attempts have shown that the utilization of base (Table 1, entry
5-6) restrict the reaction process, even with longer reaction
time. To our delight, superior conditions were found with
shorter reaction time without heating. In the optimal protocol,
1.5 equivalent of CDI was added to a solution of azido-Ugi
product in DCM at room temperature under air, and the
corresponding oxazinanone was formed with nearly
quantitative yield in a few hours (Table1, entry 9).
1
2
3
4
5
6
7
8
dominant moieties in plenty of valuable chemicals and
therapeutic agents in modern drug discovery and material
science development.9 Cyclic carbamate moieties are not only
present in many drugs (Figure 1B), but also play important
roles in several chemicals progresses as chiral auxiliaries10,11
,
and in the preparation of hyper branched polymers12,13. In
particular, 6-membered (2-oxazinanone) cyclic carbamates has
cumulatively been regarded as privileged scaffolds in drug
discovery due to excellent chemical stability and cell
membranes permeability. Owing to the prominent medicinal
and industrial applicability of cyclic carbamates, various
synthetic routes have been exploited (Figure 1C)14. The
classical approaches generally involve either phosgene and its
derivatives15,16, alkyl halide chemistry17, or sacrificial rea-
gents18, such as urea and organic carbonates. Shortly afterward,
several other synthetic approaches have been developed to
supersede these dissipative, costly and environment hazardous
methods. Nevertheless, the following reactions confront various
defects, for instance, harsh reaction conditions (0°C or
heating)19, catalyst requirement20, difficult to access starting
materials21,22, long reaction time23, multiple steps24, low
yields25, and limited scope26.
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Scheme 1. Yields of the Ugi Products (1) and cyclized 1.3-
oxazinan-2-one (2)
N
N
N N
N
N
N
R2
N
O
H2N R1
R2
CDI(1.5 equiv)
DCM, rt, 3-12h
MeOH
rt, 18h
OH
R1
R1
O
+
N
N
CN R2
TMSN3
H
OH
O
R3
R3
R3
2a-2o
1a-1o
Our strategy for a cyclization-induced property change based
on MCR chemistry was to use bifunctional orthogonal amino
and hydroxyl aldehydes in specific variants of the Ugi reaction,
GBB-3CR and UT-4CR, followed by a secondary cyclization
on the intermediates to yield (thio) carbamates, ureas and amino
sulfonic acid esters of 6- and 7-membered ring size (Figure
1D).
N
N
N
N
N
N
N
N
N
N
2a
O
O
O
O
2b
2a
2b
B
a
b
A
B
:75% , :99%
A
:98%, :72%
N
N
N
N
N
N
N
N
N
N
N
N
O
N
N
■ RESULTS AND DISCUSSION
Table 1. Optimization of reaction conditionsa
N
O
O
O
O
O
O
2d
2e
2c
B
A
B
:84%, :85%
A B
:64%, :73%
A
:97%, :47%
N
N
N
N
N
N
N
N
CDI
N
N
N N
N
N
N
N
N
N
conditions
H
O
O
OH
N
N
2a
1a
O
O
O
O
equiv. of
CDI
2f
2g
2e
entry
base
time (h)
t (oC)
yield (%)b
A
B
:76%, :66%
A
B
:20%, :72%
1
2
3
4
5
6
7
8
9
1
1
2
2
2
2
2
1.2
1.5
-
-
-
-
3
3
3
rt
50
rt
50
rt
rt
rt
rt
rt
76
83
93
88
61
71
48
85
99
O
N
N
N
N
N
N
N N
O
N
N
N
N
N
N
N
N
HN
O
3
N
N
N
N
TEA
DIPEA
NaHCO3
12
12
12
3
O
O
O
O
O
O
O
O
2h
2k
B
2j
2i
A
:66%, :75%
A
B
A:82%, B:68%
:31%, :70%
A
B
:98%, :67%
-
-
3
N
N
N
N
aThe CDI conducted reaction was carried out in DCM with
N
N
N
N
2k
1M concentration; bIsolated yields.
O
2m
N
N
O
O
Br
O
O
2l
2m
The azido-Ugi product 1a, which features a secondary amine,
was chosen as the model substrate to verify this hypothesis.
Salicylaldehyde aldehyde was selected in this azido-Ugi
reaction as the supplier of the free hydroxyl group. 1,1'-
Carbonyldiimidazole (CDI) is a coupling reagent mainly used
for the synthesis of amides, peptides, carbamates as well as
ureas.27,28 Therefore, we envisioned that CDI could enable the
desired cyclic carbamate formation by affording the carbonyl
group to the MCR product. Having synthesized the
A
B
:58%, :95%
A
B
:56%, :89%
N
N
N N
N
N
N
N
N
N
N
N
O
O
N
N
N
O
O
O
O
O
O
Br
2p
2o
A:57%, B:99%
2n
A
B
:54%, :75%
A
B
:30%, :99%
aIsolated yield of 1; bIsolated yield of 2
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Under optimized conditions, we next examined the substrate
1
2
3
4
5
6
7
8
scope of cyclization with various amines, isocyanides, and
salicylaldehydes with diverse substitutions (Scheme 1). The
majority of the corresponding oxazinanones resulted in
moderate to good yields over two steps. First of all, amino
substituents have obvious influences on synthetic conversion.
Compounds synthesized by aromatic amines exhibited
excellent overall yields, including phenox phenyl substituted 2e
despite the possible steric hindrance. On the contrary, aliphatic
amine substitutions reduced the yield of the cyclization. For
instance, compound 2c with allyl substitution affords only 47%
yield. In addition, changes in the isocyanide components were
well-tolerated. Most of the isolated products have
approximately 70% yield. It is noteworthy that the desired
compound 2i was obtained in high yield in the presence of a
competitive amino group in the indole ring. Furthermore,
aldehydes with methoxyl and halogen substituents on ortho- or
meta- positions were evaluated in the scope as well.
Surprisingly, most of the cyclization products with either mono-
or multi- substituents on the salicylaldehydes gave
extraordinary quantitive yields.
Scheme 3. Substrate Scope of cyclized 1,3-oxazinane-2-
thiones and 1,3-oxazepane-2-thiones (5)
O
O
N
N
N
N
N
N
N
N
S
DCM, rt
77%a
N
N
N
N
+
N
N
H
OH
O
S
5a
N
N
9
N
N
N
N
S
N
N
10
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60
DCM, rt
N
N
NH
OH
+
N
N
N
89%
O
S
N
O
5b
O
N
N
N
S
N
N
N
O
OH
DCM, rt
84%
NH
N
N
N
N
+
S
5c
aIsolated yield of cyclic thiocarbamate 5.
In light of the aforementioned results, we next explored the
synthesis of thiocarbamate derivatives (Scheme 3). 1,1'-
Thiocarbonyldiimidazole (TCDI), the sulfur analog of CDI,
was employed as the thiocarbonyl donor. Accordingly, the
reaction was conducted with 2 equivalents of TCDI in room
temperature for 12h in DCM. To our delight, the overall
cyclization exhibited good to excellent yields. Positively,
enhanced conversion to the thiocarbamate compounds was
observed in the Ugi products, compared with the carbamate
formation. Furthermore, it is noteworthy that the thiocarbamate
GBB product (5c, 84%) went better than carbamate GBB (4a,
22%), effectively comparable with the Ugi product yields (5a,
77%; 5b, 89%).
Scheme 2. Yields of the GBB Products (3) and cyclized
oxazepanones (4)
R3
O
R3
N
N
R4
X
NH2
CH3CN
CDI(1.5 equiv)
DCM, rt, 12h
OH
X
R4
N
R3
N
O
N
m.w. 110oC 20min
N
R2
R4
CN R2
HO
+
NH
R2
X
0.08equiv HCl in dioxane
O
4a-4c
3a-3c
N
N
N
N
N
N
N
N
O
O
O
N
N
N
O
O
O
4c
4a
4b
a
b
A B
:97%, :47%
A
B
A
B
:86% , :22%
:78%, :42%
aIsolated yield of 3; bIsolated yield of 4
Scheme 4. Substrate Scope of cyclized 1,2,3-oxathiazinane-
2,2-dioxides and 1,2,3-oxathiazepane-2,2-dioxides (6)
Encouraged by the initial results, we investigated the
potential of the cyclization strategy based on Groebke-
Blackburn-Bienaymé reactions (GBB reactions) which could
afford secondary amines on imidazole heterobicyclic rings
(Scheme 2).2,3,4 Equimolar amounts of aldehyde, amino amine
and isocyanide, as well as 0.08 equivalent of HCl in dioxane,
were combined in CH3CN (1 M) in microwave at 110 °C for 20
min. The corresponding imidazole-heterobicyclic product 3
was isolated by column chromatography with excellent yields
(for example, 3c, 97%). The identical cyclization approach as
above was employed. Not surprisingly, the carbamate
formation of the 7-membered 1,3-oxazepan-2-one appeared
more difficult than the 6-membered 1.3-oxazinan-2-ones. The
overall yields of the cyclized GBB products are below 50%. A
large amount of imidazole-1-carboxylate intermediates were
observed even with longer reaction time.
N
N
N
N
N
N
N
N
N
Cs2CO3
O
N
S
+
N
S
N
N
O
CH3CN, rt
45%a
H
N
O
O
O
OH
6a
N
N
N
N
N
O
N
Cs2CO3
O
N
N
S
N
OH
S
O
+
NH
O
N
CH3CN, rt
33%
O
N
6b
aIsolated yield of cyclic thiocarbamate 6.
Next, we attempted to use the uniform approach with the
sulfonyl donor 1,1’-Sulfonyldiimidazole (SDI), for the
synthesis of sulfamate derivatives (Scheme 4). However, under
the previous conditions, the reaction remained at the stage of
the imidazole-1-sulfonyl intermediate instead of cyclization to
the sulfamate product. In order to push the reaction to the
desired cyclization, excess amount of Cs2CO3 was added to the
reaction solution. Under base-catalysis, 6-membered and 7-
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membered cyclized sulfamate derivatives were then
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medicinal chemistry, were identified as the most relevant
descriptors (black arrows) to explain the variance among the
cyclic and non-cyclic molecules, indicating drug-likeliness of
all herein described cyclic scaffolds.
1
2
3
4
5
6
7
8
synthesized in 45% (6a) and 33% (6b) yield, respectively.
Scheme 5. Substrate Scope of 5-membered CDI cyclization
of MCR products (8)
O
N
N
N
N
N
R2
R3
N
R3
X
N
N
■ CONCLUSION
R2
R3
CDI(1.5 equiv)
DCM, rt, 3h
CN R2
TMSN3
MeOH
rt, 18h
R4
R1
+
N
R1
N
In summary, a MCR-based synthesis of 5-membered, 6-
membered and 7-membered cyclic carbamate derivatives with
at least 4 substitutions has been developed with the purpose to
modify physicochemical properties. Both the azido-Ugi
reaction and the GBB reaction are instrumental in this approach,
leading to potentially bioactive bis-heterocyclic or multi-
heterocyclic scaffold constructs. Furthermore, their thio- and
sulfur- scaffolds are investigated along with the achievement of
extraordinary scaffold diversity. The cheminformatics analysis
clearly shows we are addressing a drug-like chemical space.
Our protocol, utilizing mild condition and readily available
building blocks, is of excellent maneuverability, scalability, and
efficiency. It will add to a growing body in the development of
material and organic synthesis, as well as medicinal chemistry.
X
H
R1
R4
X
H2N
R4
O
7a-7c
8a-8c
9
N
N
N
N
N
N
N
N
N
N
10
11
12
13
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22
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60
N
N
N
8a
N
N
N
O
N
N
O
O
O
8a
8c
8b
a
b
A
B
:60% , :74%
A
B
:80%, :60%
A
B
:74%, :99%
aIsolated yield of 7; bIsolated yield of 8
As an application of this methodology, we next investigated
the scope of 5-membered carbamate cyclization and urea
cyclization with CDI as the carbonyl donor (Scheme 5). The
main innovation of 5-membered ring formation is the
employment of various aldehydes. Glycolaldehyde dimer,
providing a free hydroxyl group, was used in the azido-Ugi
reaction. CDI afforded oxazolidin-2-one 8a with 74% yield.
Pyrrole-2-carboxaldehyde and 2-imidazolecarboxaldehyde,
which provided secondary amines, were employed to the
formation of heterobicyclic ureas with 99% (8b) and 60% (8c)
yield, respectively. For better yields, a catalytic amount of
DIPEA was added in the urea formation.
■ ASSOCIATED CONTENT
Supporting Information
NMR spectra, crystal structure determinations and chemical space
exploration are included as Supporting Information. This material
is available free of charge via the Internet at http://pubs.acs.org.
Additionally, five oxazinanone derivatives (2a, 2b, 2e, 2k,
2m) and one oxazolidinone derivative (8a) have been
confirmed by X-ray single-crystal analysis (Scheme1, Scheme
5 and Supporting Information).
■ AUTHOR INFORMATION
Corresponding Author
* a.s.s.domling@rug.nl, www.drugdesign.nl
ORCID
Jingyao Li: 0000-0002-9357-9896
Pravin Patil: 0000-0002-0903-8174
Angel J. Ruiz Moreno: 0000-0002-2798-5386
Alexander Dömling: 0000-0002-9923-8873
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
Notes
Figure. 2 Normalized PC1 vs PC2 plot of cyclic and non-
cyclic molecules. Cyclic molecules (green) showed a different
distribution against non-cyclic molecules (pink).
The authors declare no competing financial interest.
To exemplify the scaffolding induced property modulation,
we compared 14 physicochemical properties of each 1000
compound virtual libraries30,31 of the cyclized and non-cyclized
structures (Figure 2 and Supporting Information). PCA of
five non-redundant physicochemical properties included 3D
descriptors allowed us to identify interesting differences
between non-cyclic and cyclic molecules. Topological polar
surface area (TPSA) and logP, which are important values in
■ ACKNOWLEDGMENTS
This research has been supported to (AD) by the National
Institute of Health (NIH) (2R01GM097082-05), the European
Lead Factory (IMI) under grant agreement number 115489, the
Qatar National Research Foundation (NPRP6-065-3-012).
Moreover, funding was received through ITN “Accelerated
Early stage drug dIScovery” (AEGIS, grant agreement No
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an N-Acyl Quaternary Ammonium Intermediate. J. Org.
Chem. 1968, 33(4), 1367-1371.
Dao Thi, H.; Le Nhat Thuy, G.; Catak, S.; Van
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