Synthesis of Diversely Substituted Imidazolidines via [3+2] Cycloaddition of 1,3,5-Triazinanes with Donor-Acceptor Aziridines and Their Anti-Tumor Activity

Article abstract of DOI:10.1002/adsc.202001569

A Y(OTf)₃-catalyzed [3+2] cycloaddition of 1,3,5-triazinanes with donor-acceptor aziridines has been developed, accessing diversely substituted imidazolidines high efficiency. Mechanistic investigations support the formation of imidazolidines through an S_N1-like pathway. Furthermore, these imidazolidines exhibit promising anti-tumor activity against a series of human cancer cell lines. (Figure presented.).

Full text of DOI:10.1002/adsc.202001569

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DOI: 10.1002/adsc.202001569
Synthesis of Diversely Substituted Imidazolidines via [3+2]
Cycloaddition of 1,3,5-Triazinanes with Donor-Acceptor
Aziridines and Their Anti-Tumor Activity
Zhichao Shi,+a, b Tingting Fan,+b, c, d Xun Zhang,a, b Feng Zhan,a, b Zhe Wang,a, b
Lei Zhao,a, b Jin-Shun Lin,a, b,* and Yuyang Jianga, b, c, d, e,
*
a
Department of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China
E-mail: lin.jinshun@sz.tsinghua.edu.cn; jiangyy@sz.tsinghua.edu.cn
The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International
Graduate School, Tsinghua University, Shenzhen 518055, People’s Republic of China
Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, People’s Republic of China
Shenzhen Bay Laboratory, Shenzhen 518055, People’s Republic of China
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, People’s Republic of China
b
c
d
e
+
These authors contributed equally to this work.
Manuscript received: December 17, 2020; Revised manuscript received: February 25, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001569
Abstract: A Y(OTf)3-catalyzed [3+2] cycloaddition of 1,3,5-triazinanes with donor-acceptor aziridines has
been developed, accessing diversely substituted imidazolidines high efficiency. Mechanistic investigations
support the formation of imidazolidines through an SN1-like pathway. Furthermore, these imidazolidines
exhibit promising anti-tumor activity against a series of human cancer cell lines.
Keywords: Imidazolidines; Cycloaddition; Donor-acceptor aziridines; 1,3,5-Triazinanes; Anti-tumor activity
Introduction
Imidazolidine and imidazoline frameworks are charac-
teristic and essential motifs embedded in an array of
agrochemical fungicides,[1] pharmaceuticals[2] and
ligands[3] (Scheme 1). Consequently, direct construc-
tion of diversely substituted imidazolidines has long
been recognized as a preeminent goal for organic
synthesis. Several approaches are known to synthesize
imidazolidines,[4] involving mannich cyclization,[5] in-
tramolecular amination and the metal-catalyzed or
metal-free protocols for multicomponent reactions[6] or
formal cycloaddition.[7] Among them, intermolecular
Scheme 1. Representative biologically active compounds and
ligands.
[3+2] cycloaddition[8] is a viable strategy for synthesis
of these valuable functionalized imidazolidines in an
atom-economical fashion.
Donor-acceptor (DÀ A) aziridine, a versatile syn- the presence of Lewis acids.[10] In this field, Feng X
thetic building block in organic synthesis, is applicable and co-workers have developed the chiral N, N’-
to the construction of five-membered nitrogen hetero- dioxide/Lewis acid-catalyzed enantioselective [3+2]
cycles via [3+2] cycloaddition with diverse annulation of donor-acceptor aziridines with
nucleophiles,[9] which prefers CÀ C bond cleavage in aldehydes,[11a] 3-methylindoles,[11b] 3,4-dihydropyran
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derivatives or acyclic enol ethers[11c] respectively for access
to
functionalized
imidazolidines
the construction of enantioenriched nitrogen hetero- (Scheme 2b).[19] Despite these achievements, to the best
cycles. Additionally, Zhang and co-workers have of knowledge, the cycloaddition of donor-acceptor
reported a formal [3+2] cycloaddition of donor- aziridines and 1,3,5-triazinanes has not been demon-
acceptor aziridines with stable Bn-/Ph-substituted strated so far. Herein, we disclose the first Y(OTf)3
imines to afford the multisubstituted imidazolidines.[12] catalyzed [3+2] cycloaddition of donor-acceptor azir-
Recently, we have achieved the first [3+2] cyclo- idines and 1,3,5-triazinanes via CÀ C bond cleavage to
addition of donor-acceptor aziridines and nitriles provide a range of diversely substituted imidazolidines,
mediated by Brønsted acid via CÀ N cleavage to afford which show promising anti-proliferative activity
tetrafunctionalized 2-imidazolines.[13] Furthermore, as against a number of human cancer cell lines (Sche-
part of our continuous efforts to construct the five- me 2c).
membered azaheterocycles,[14] we become interested in
developing the reactions of the donor-acceptor azir-
idines and other nucleophiles to construct the potential
Results and Discussion
bioactive five-membered azaheterocycles.
Inspired by Liu’s earlier work on ZnBr2-catalyzed 1,3-
1,3,5-Triazinanes, as stable and readily available dipolar cycloadditions of 1,3,5-triazinanes with
surrogates of formaldimines, were utilized in various aziridines,[19] donor-acceptor aziridine 1a and triazine
nitrogen-containing heterocycle construction with vari- 2a were utilized as model substrates to optimize
ous nucleophiles.[15] Most of the reactions of 1,3,5- reaction conditions (Table 1). However, the reaction in
triazinanes reported so far are involved in aminometh- the presence of ZnBr2 with toluene as the solvent
ylations[16] and cycloaddition reactions.[17] Seminal provided the desired product 3A in poor yield
work catalyzed by Lewis acid was performed by Werz (entry 1), and the reaction yield was increased to 72%
and co-workers, who reported the cycloadditions of by using 4 Å MS as an additive, thus indicating the
1,3,5-triazinanes and donor-acceptor cyclopropanes/
cyclobutanes (Scheme 2a).[18] Recently, Liu group
presented the elegant Lewis acid catalyzed [3+2]
Table 1. Optimization of the reaction conditions.[a]
cycloadditions of aziridines and 1,3,5-triazinanes to
Entry
Catalyst
Solvent
Yield[b] (%)
1[c]
2[d]
3[e]
4[e]
5
6
7
8
9
10
11
12
13[f]
14[g]
15[h]
ZnBr2
ZnBr2
TfOH
Toluene
Toluene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
42
72
nd
nd
8
42
16
72
42
98
36
4
BF3 ·Et2O
Cu(OTf)2
Fe(OTf)3
Zn(OTf)2
Mg(OTf)2
Ni(OTf)2
Y(OTf)3
Yb(OTf)3
AgSbF6
Y(OTf)3
Y(OTf)3
Y(OTf)3
94
96
92
[a] Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol),
catalyst (10 mol%), 4 Å MS (25 mg), solvent (0.5 mL); for
more optimizated reaction conditions, see the SI.
[b] Yields were determined via 1H NMR by using CH2Br2 as the
internal standard.
[c]
°
80 C, no 4 Å MS.
[d]
°
80 C.
[e] Complex mixture. nd: not determined.
[f] Solvent (1 mL).
[g] Catalyst (5 mol%).
[h] 2a (0.02 mmol), catalyst (5 mol%).
Scheme 2. The cycloaddition of 1,3,5-triazinanes.
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deleterious effect of water in the process. Inspired by
our previous work,[13] TfOH and BF3 ·Et2O were chose
as the catalysts, unfortunately, they were completely
ineffective in the present reaction (entries 3–4). Then
we screened other commercially available Lewis acids,
and found Y(OTf)3 was most beneficial for the
reaction, resulting in 98% yield (entry 10). Next, a
solvent screen revealed DCM to be optimal, and
decreasing the concentration of the reaction resulted in
a yield of 94% (entry 13) (See Table S1 in SI for more
details). We next studied this reaction with different
loadings of Y(OTf)3 under the optimal reaction
conditions and found that the load could be reduced to
5 mol% without any remarkable effect on the yield of
3A (entry 14). To our surprise, when 2a was reduced
to 0.4 equiv., the desired product 3A was also obtained
in 92% yield (entry 15), which indicated that our
approach featured excellent atom-economy compared
with the previous Werz’s[18] and Liu’s[19] work. After
the investigation of other reaction parameters, we
established the optimized reaction conditions as 1a
(0.05 mmol), 2a (0.02 mmol), Y(OTf)3 (5 mol%), 4 Å
Table 2. Substrate scope of [3+2] cycloaddition of donor-
acceptor aziridines with 1,3,5-triazinanes.[a,b]
°
MS (25 mg), DCM (0.5 mL), at 30 C for 12 h.
We explored the scope and limitations of the
reaction by using various donor-acceptor aziridines
and 1,3,5-triazinanes under the optimized reaction
conditions, and the results are summarized in Table 2.
All the donor-acceptor aziridines and 1,3,5-triazinanes
underwent the cycloaddition smoothly to give the
corresponding products in excellent yields. Imidazoli-
dines 3A–3K bearing electronically neutral or elec-
tron-rich groups at the ortho, meta or para position of
the aryl ring were obtained in good yields. Particularly
noteworthy is that alkynyl substituents 1h and 1i were
well-tolerated, which is significant since aryl alkynyl
groups are usually incompatible with Lewis acid-
catalyzed cycloaddition of donor-acceptor aziridine
systems.[9] The structure of 3I was unambiguously
confirmed by X-ray crystallographic analysis (Fig-
ure S1 in SI).[20] Meanwhile, variation on the substitu-
tion of the arylsulfonyl group also furnished the
[a] Reactions were conducted on 0.2 mmol scale.
[b] Isolated yield based on 1 is given.
corresponding products in moderate yields. 1l–1n providing the corresponding products 3AA–3AC in
bearing electron-withdrawing groups and electron- 66%–71% yield.
donating groups of the aryl ring participated in the
To further demonstrate the utility and practicality of
reaction well to provide 3L–3N respectively. Addition- this protocol, this [3+2] cycloaddition was conducted
ally, for the ester moieties, the reactions of aziridines on gram-scale. The reaction of 1a with 2g could be
1o–1q also worked very well under standard con- easily run on the gram scale in a good yield of 98%
ditions to give the corresponding products in moderate (Scheme 3a). On the other hand, the removal of the
yields, indicating the ester group does not affect the benzenesulfonyl group and elimination of the acetoxy
reaction. Furthermore, various 1,3,5-triazinanes also group of 3W were carried out to afford the imidazoline
engaged in efficient cycloaddition, and high yields derivative 4 (Scheme 3b),[21] which is a scaffold of
were observed for substrates bearing electron-with- biologically active compound[2b–d] (Scheme 1).
drawing/donating groups at the para, ortho or meta
To obtain some insights into the reaction mecha-
position of the phenyl ring to afford products 3R–3Z. nism, we explored the stereospecificity of the reaction
Additionally, it is noteworthy that this transformation using enantioenriched DÀ A aziridine (R)-1a (97%
was also applicable to the substituted 1,3,5-triazinanes ee).[18] Indeed, the corresponding racemic product 3A
bearing pyridinyl, methyl and cyclopropyl group, was obtained with 3% ee, which indicated that the
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heterocycles,[14,24] we next proceeded to investigate the
catalytic asymmetric [3+2]-cycloaddition of 1,3,5-
triazinanes with racemic donor-acceptor aziridines by
using our recently developed copper salts and CPA
(chiral phosphoric acids) cooperative catalysis
system.[24] To our delight, after screening of some
commercial available chiral phosphoric acids, the (R)-
VAPOL was turned out to be the most effective
catalyst, providing 78% yield and 31% ee (Scheme 6).
The preliminary positive result demonstrated that this
catalytic asymmetric reaction was feasible via a
cationic intermediate.
Finally, considering the importance of the con-
structed imidazolidine scaffold in pharmaceutical
chemistry, we randomly selected a number of imidazo-
lidines for the evaluation of anti-proliferative activity
Scheme 3. Synthetic application.
cycloaddition could proceed through a SN1 model in different human cancer cell lines (Table 3, Ta-
(Scheme 4). ble S2). In human histiocytic lymphoma cell line
Here, a general mechanism for the formal [3+2] (U937), most of the tested compounds exhibited anti-
cycloaddition was proposed. As depicted in Scheme 5, proliferative activity with moderate inhibitory concen-
in the presence of Y(OTf)3, the formaldimine A was tration (IC50) values. Compounds 3B and 3O also
first generated[22] and the 1,3-dipole B was produced effectively inhibited the proliferation of human cer-
in situ from the ring-opening reaction of the donor- vical carcinoma (Hela), breast cancer (MCF-7), lung
acceptor aziridine 1a, followed by a [3+2] cyclo- cancer (A549) and epidermoid carcinoma (A431) cell
addition between the formaldimine A and 1,3-dipole lines (Table S4). Besides, compound 3B also displayed
B, furnishing the desired product 3A through an SN1- median inhibitory effect in human chronic myeloid
like pathway.[23]
leukemia cell line (K562) and human breast cancer cell
After completing the racemic version, as part of our line (MDA-MB-231). Notably, compound 3B showed
continuous efforts in catalytic asymmetric transforma- impressive anti-proliferative activity in these cancer
tions for the construction of potentially bioactive aza- cell lines with IC50 values. Furthermore, the cytotox-
icity of compound 3B against human normal colonic
epithelial cell line (FHC) and human normal hepatic
cell line (HL-7702) were also evaluated, interestingly,
compound 3B was found to be less toxic in comparison
to Combretastatin A4 (CA-4) and Paclitaxel in human
normal cell lines (Table S3, SI). Therefore, compound
3B might be a promising compound for discovering
more applications in medicinal chemistry.
Scheme 4. Stereochemistry and mechanistic investigation.
Conclusion
In summary, we have reported a formal [3+2] cyclo-
addition of donor-acceptor aziridines with 1,3,5-
triazinanes catalyzed by Y(OTf)3, providing diversely
Scheme 5. Plausible reaction mechanism.
Scheme 6. Catalytic asymetric [3+2] cycloaddition reaction.
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Table 3. Anti-proliferative activity in human cancer cell lines.
Compound
IC50 (μM)[a]
U937
Hela
MCF-7
A549
K562
MDA-MB-231
3A
3B
3C
3I
3K
3L
3N
3O
10.8�3.4
11.6�2.1
11.8�1.7
8.2�3.9
>25
>25
20.1�2.5
9.4�4.2
13.5�3.4
>25
>25
10.1�3.3
20.2�7.3
9.6�3.0
8.9�2.9
18.0�2.2
22.4�7.9
13.2�4.2
>25
9.2�1.2
13.5�4.6[c]
21.5�7.1[c]
9.9�3.3
9.4�2.9
16.2�10.4
>25
21.7�6.6
>25
>25
>25
>25
>25
>25
10.6�1.9
>25
>25
>25
>25
23.0�14.4
>25
>25
>25
9.5�2.7
9.3�5.4
14.2�10.1
22.7�13.1
15.8�16.1
0.8�0.2[c]
1.0�0.4[c]
>25
>25
12.6�9.8
9.0�6.1
>25
17.5�2.7
4.2�1.4
60.9�39.4[c]
3.0�2.8[c]
3Y
>25
>25
CA-4[b]
Paclitaxel[b]
2.2�1.7[c]
2.9�0.8[c]
8.2�1.8[c]
7.2�6.5[c]
13.8�2.9[c]
7.6�6.0[c]
[a] IC50 values were measured by the MTT assay upon 72 h compounds treatment. Data are expressed as the mean � SD (standard
error) from the dose response curves of three independent experiments. The IC50 value is the concentration of a compound that
was able to cause 50% cell death with respect to the control culture.
[b] Used as the positive control.
[c] The unit of IC50 for CA-4 and Paclitaxel is nM.
absorbance was measured by a microplate reader (Tecan infinite
substituted imidazolidines in high yields under mild
conditions. More importantly, the compound 3B
exhibited promising anti-proliferative activity against a
number of human cancer cell lines, which could serve
as a hit compound for the anti-tumor research. Further
catalytic asymmetric transformation and more studies
on biological activity are ongoing in our laboratory.
M1000 Pro) at 490 nm.
Acknowledgements
This work was supported by Shenzhen Development and Reform
Committee (No. 2019156), Shenzhen Science, Technology and
Innovation Commission (JCYJ20180306174248782), Depart-
ment of Science and Technology of Guangdong Province (No.
2017B030314083) and Shenzhen Bay Laboratory Open Fund-
ing (SZBL2019062801009).
Experimental Section
General Procedure for the Synthesis of Products
3 A-3Z
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