Desymmetrization of Cyclic 1,3-Diketones under <i>N</i>-Heterocyclic Carbene Organocatalysis: Access to Organofluorines with Multiple Stereogenic Centers

Desymmetrization of Cyclic 1,3-Diketones under N-Heterocyclic Carbene Organocatalysis: Access to Organofluorines with Multiple Stereogenic Centers

PDF

Guanjie Wang¹, Min Zhang², Yezhi Guan³, Ye Zhang¹, Xianfang Hong¹, Chenlong Wei¹, Pengcheng Zheng⁴, Donghui Wei², Zhenqian Fu¹, Yonggui Robin Chi⁴^,⁵, Wei Huang¹^,⁶

Research. Vol 2021 Article ID 9867915

Less

Research. Vol 2021 Article ID 9867915

• Research Article •

Desymmetrization of Cyclic 1,3-Diketones under N-Heterocyclic Carbene Organocatalysis: Access to Organofluorines with Multiple Stereogenic Centers

Full

Guanjie Wang¹, Min Zhang², Yezhi Guan³, Ye Zhang¹, Xianfang Hong¹, Chenlong Wei¹, Pengcheng Zheng⁴, Donghui Wei², Zhenqian Fu¹, Yonggui Robin Chi⁴^,⁵, Wei Huang¹^,⁶

Affiliations

¹Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM) Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, China

²College of Chemistry and Green Catalysis Center, Zhengzhou University, Zhengzhou, Henan 450001, China

³School of Chemistry and Molecular Engineering, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, China

⁴Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China

⁵Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore, Singapore, 637371

⁶Frontiers Science Center for Flexible Electronics (FSCFE) & Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical University (NPU), 127 West Youyi Road, Xi’an 710072, China

About Author:

Authors’ Contributions

Z.F. conceived the idea and designed the experiments. Z.F., D.W., R.Y.C., and W.H. supervised the work. G.W. conducted most of the experiments. Y.Z., X.H., and C.W. prepared some of starting materials. M.Z. performed the DFT study. Y.G. and P.Z. performed antibacterial activity tests. Z.F. drafted the manuscript with assistance from all coauthors. All authors contributed to discussions.

Published: 2021-08-20 doi: 10.34133/2021/9867915

Outline

Abstract

Less

Symmetric 1,3-diketones with fluorine or fluorinated substituents on the prochiral carbon remain to be established. Herein, we have developed a novel prochiral fluorinated oxindanyl 1,3-diketone and successfully applied these substrates in carbene-catalyzed asymmetric desymmetrization. Accordingly, a versatile strategy for asymmetric generation of organofluorines with fluorine or fluorinated methyl groups has been developed. Multiple stereogenic centers were selectively constructed with satisfactory outcomes. Structurally diverse enantioenriched organofluorines were generated with excellent results in terms of yields, diastereoselectivities, and enantioselectivities. Notably, exchanging fluorinated methyl groups to fluorine for this prochiral 1,3-diketones leads to switchable stereoselectivity. Mechanistic aspects and origin of stereoselectivity were studied by DFT calculations. Notably, some of the prepared organofluorines demonstrated competitive antibacterial activities.

Cite this Article

Guanjie Wang, Min Zhang, Yezhi Guan, Ye Zhang, Xianfang Hong, Chenlong Wei, Pengcheng Zheng, Donghui Wei, Zhenqian Fu, Yonggui Robin Chi, Wei Huang. Desymmetrization of Cyclic 1,3-Diketones under N-Heterocyclic Carbene Organocatalysis: Access to Organofluorines with Multiple Stereogenic Centers[J]. Research, 2021 , 2021 (8) : 9867915 - . DOI: 10.34133/2021/9867915

Full Text

Less

1. Introduction

Less

Asymmetric desymmetrization represents one of the most facile and efficient methods for the generation of enantioenriched organic compounds, especially with multiple stereogenic centers, from meso or prochiral raw materials [1–4]. In this area, catalytic desymmetrization of prochiral 1,3-diketones has been investigated widely, including asymmetric reduction, intramolecular adol-type reactions, and others [5–21]. Furthermore, this desymmetric strategy as the key step has shown wide application in diverse natural product synthesis associated with diverse promising biological activities [22, 23]. Owing to privileged structural characters of prochiral 1,3-diketones, such as containing unique and versatile carbonyl groups, and easily introducing substituents, further development of novel diverse prochiral diketones and their desymmetric strategies is still of high importance. Organic molecules with fluorine or fluorinated substituents can significantly change their physical, chemical, and biological properties [24–29]. For example, fluorocortisone, the first fluorine-containing pharmaceutical, possesses remarkable glucocorticoid activity that exceeds the activities of the parent hormones by a factor of 10 [30]. Although fluorine is the 13th most common element in the earth’s crust, it mainly exists as inorganic salts. Indeed, the number of biogenic organofluorines is extremely limited (around 20) [31]. Therefore, organofluorine synthesis and application have received tremendous attention in organic chemistry and achieved great advances [32–36]. Currently, a large number of pharmaceuticals and agrochemicals involve at least one fluorine atom. Surprisingly, symmetric 1,3-diketones with fluorine or fluorinated substituents on the prochiral carbon are largely overlooked and remain to be established (Figure 1(a)).

Notably, prochiral 1,3-diketones possess several privileged advantages, including the following: (i) The acidic prochiral carbon can be easily functionalized by deprotonation with various commercially available fluorination reagents (F, CF₃, CF₂H, CH₂F, etc.) [37–42]. Catalytic asymmetric desymmetrization of these substrates ensures a versatile method for the synthesis of enantioenriched organofluorines. Actually, it is challenging to be compatible with fluorine and fluorinated substituents in one asymmetric reaction due to their distinct properties. (ii) Asymmetrically modifying one of the two ketone carbonyl groups leads to the formation of fluorine-containing multiple stereogenic centers. Notably, the synthesis of such great challenging motifs has been largely underdeveloped, although they have already appeared in several invaluable pharmaceuticals (Figure 1(c)) [36].

Given the significant success of asymmetric N-heterocyclic carbene (NHC) catalysis [43–52] and privileged structural characters of prochiral 1,3-diketones, based on our ongoing interest in organocatalysis [53–57], we envisioned that a versatile method for the synthesis of enantioenriched organofluorines with multiple stereogenic centers might be established based on NHC-catalyzed asymmetric desymmetrization of novel prochiral fluorinated or fluoromethylated oxindolyl 1,3-ketones. Notably, asymmetric synthesis of spirocycle compounds has attracted a lot of synthetic attention [58–61]. Among them, spiro compounds containing oxindole moieties are proven among the important scaffolds in natural products and bioactive molecules exemplified by those in Figure 1(d) [61, 62]. These easily available prochiral 1,3-diketones could react with unsaturated acyl triazolium intermediates [63–65] obtained from bromoenals with NHC to construct spiropolycyclic organofluorines with five stereogenic centers, including three quaternary stereocenters. While one requirement would be to achieve intermolecular domino desymmetrization, the connection of the reactive site (carbonyl group) to a sterically hindered quaternary carbon center may impede this process. Furthermore, the ability to achieve satisfactory diastereoselectivity and enantioselectivity would remain important. Importantly, organocatalyzed generation of enantioenriched organofluorines prevents heavy metal residues, considerably increasing the potential utilities. We herein have developed a novel prochiral fluorinated oxindanyl 1,3-diketone and successfully applied these substrates in carbene-catalyzed asymmetric desymmetrization. Accordingly, a versatile and practical strategy for asymmetric generation of organofluorines with fluorine or fluorinated methyl groups (CF₃, CF₂H, or CH₂F) has been developed. Multiple stereogenic centers were selectively constructed with satisfactory outcomes. It may be mentioned that enantioselective synthesis of tricyclic β-lactones by NHC-catalyzed desymmetrization of cyclic 1,3-diketones has been demonstrated recently by Shee and coworkers [66].

2. Results

Less

We initially attempted this synthetic approach with prochiral trifluoromethylated oxindolyl 1,3-diketone 1a and (Z)-2-bromo-3-phenylacrylaldehyde 2a under NHC organocatalysis. Trifluoromethylated spiropolycyclic compound 3a was obtained in 11% yield when sterically hindered aminoindanol-derived triazolium precatalyst A was employed in the presence of K₂CO₃ in toluene at room temperature (Table 1, entry 1). Subsequently, several bases were screened, and sodium acetate was the best base, giving the product 3a in good yield (82%) with >20 : 1 dr and >99% ee (entries 2-8). Several NHC catalysts were next investigated, with NHC precatalyst B, with a Br atom on the indane moiety, proving to be the better choice to deliver the product 3a in high yield without any loss in dr or ee (entries 9–12). The yield could be further improved to 93% by using mesitylene as the solvent (entries 13-16). 5 mol% catalyst ensured this transformation to give the product in 78% yield (entry 17).

Under optimal conditions (Table 1, entry 15), the scope of this desymmetrization domino reaction was examined (Figure 2). For trifluoromethylated oxindolyl 1,3-diketones, several substituents at the 4-, 5-, 6-, and 7-positons on the oxindole ring were well tolerated to form 3a–3f in good to excellent yields (81-93%) with excellent diastereoselectivities (>20 : 1 dr values) and enantioselectivities (>99% ee values). Substrates with N-benzyl, N-allyl, and N-isopropyl groups reacted efficiently to form products 3g–3i in 83%–93% yields and without any erosion of dr values and ee values. For the indane motif, substrate 1 with a naphthalene unit gave 3j in 83% yield with >20 : 1 dr and >99% ee. Introducing two symmetrical chloride atoms to the indane ring did not influence the efficiency, furnishing the product 3k in 86% yield with >20 : 1 dr and >99% ee. Subsequently, the generality of 2-bromoenals was evaluated. For 2-bromoenals associated with electron-donating or electron-withdrawing groups on the aromatic ring, the reactions worked efficiently to afford the products 3l-3w in good to excellent yields with good to excellent diastereoselectivities and excellent enantioselectivities. Bromoenals with a naphthalene or heteroaryl unit (such as 2-furyl and 2-thienyl) were also compatible with the reaction. Unfortunately, β-alkyl-substituted enals failed to deliver the product in our reaction.

To further investigate the scope and limitations of this organocatalytic strategy, other fluorinated methyl groups, such as difluoromethyl, and monofluoromethyl groups were introduced into the prochiral substrates (Figure 3). Notably, for these substrates, the release of CO₂ could not be completely avoided under the reaction conditions and in the purification step that followed. Thus, one more decarbonation operation was performed for these substrates. Delightingly, all reactions proceeded smoothly, forming the products 6 and 8 with acceptable results. On the other hand, the intermediate underwent ring opening with a nucleophile, such as methanol, delivering products 5 and 7, respectively. We consider that asymmetric synthesis of important organofluorines containing CF₂H and CFH₂ has been overlooked to date [34, 67–69]. Our novel strategy for asymmetric synthesis of these organofluorines by carbene-catalyzed desymmetrization is effective.

After successfully documenting the synthesis of fluoromethylated molecules with five stereogenic centers under NHC organocatalysis, the generality of this desymmetrization strategy was further explored to construct fluorinated molecules (Figure 4). Different from the above-obtained products 3, 5, 6, 7, and 8, which featured the more sterically hindered fluorinated methyl groups, the resulting product 10 featured the relatively small fluorine atom and showed the opposite absolute configuration under the identical reaction conditions. In all the cases, the desymmetrization cascade process proceeded smoothly by using just 2 mol% carbene catalyst, delivering spirocyclohexene products in 86-93% yields with 2.6 : 1-11 : 1 dr and 90-99% ee values.

Under 10 mol% of NHC precatalyst B catalysis, the reaction worked efficiently on a gram scale to generate 3 g in 88% yield with >20 : 1 dr and >99% ee (Figure 5(a)). To demonstrate the practicality of the present strategy, further synthetic transformation of the resulting product was performed as shown in Figure 2. The substrates 1a with CF₃ and 9a with F underwent intramolecular desymmetrical cyclisation, followed by decarbonation to generate the corresponding products 11 and 12 in good yields with excellent dr and ee values, respectively. Impressively, our method reported here is also effective to prepare enantioenriched trifluoromethylthiolated compounds, leading to product 14 with excellent yields, dr and ee values (Figure 5(c)). Ring opening of the product 3a was achieved by treatment with nucleophiles such as methanol and benzylamine at room temperature and led to the formation of amides 15a and 15b in excellent outcomes. More importantly, for the alcohols with promising biological activities, such as cholesterol, fluphenazine, and adapalene-derived alcohol, the ring-opened products 15c-e were formed in good yields with excellent dr and ee (or de) values. The treatment of 10a with methanol under basic conditions followed by oxygen insertion converted the carbonyl moiety into a carboxylic moiety, leading to product 17 in good yield with the retention of dr and ee.

DFT calculations were conducted to explore the possible pathway. As shown in Figure 6, the carbonyl carbon of reactant 1a is susceptible to nucleophilic attack by the carbene carbon of the actual NHC catalyst via transition state TS1, which is followed by an acetic acid-mediated [1, 2]-proton transfer via transition state TS2 for the formation of Breslow intermediate M2. The third step is a bromide removal process via transition state TS3. Deprotonation can then be mediated by bromide ion, coupled with protonation by acetic acid via transition state TS4. The fifth step involves diastereoselective transition state TS5SS (or TS5RR) for Cβ–C1 bond formation between intermediate M4 and deprotonated achiral 1,3-diketone 2a^-, which is followed by an intramolecular [

2 + 2

] cycloaddition to complete the six-membered ring closure via transition state TS6SS. The two letters after the names of the stationary points represent the chirality of the molecules associated with the centrally chiral C1 and Cβ atoms. The last step is the dissociation of catalyst NHC from the main product PSS via transition state TS7SS. The Gibbs free energy barriers of the seven steps via transition states TS1-7 are 4.3, 6.3, 1.7, 18.2, 9.5 (or 12.6 for RR-configured isomer), 8.8, and 5.4 kcal/mol, respectively.

To further examine the origin of enantioselectivity, quantitative Bader atoms-in-molecules analyses were carried out. The energy barrier of transition state TS5RR is 3.1 kcal/mol higher than that of transition state TS5SS, whereas the energy barrier of the transition state TS5RR

′

is 2.2 kcal/mol lower than that of transition state TS5SS

′

(Figure 7(a)), meaning that the enantioselectivity can be switched by exchanging the -CF₃ substituent with -F. As shown in Figures 3(b) and 3(c), there are no C-H…F hydrogen bond [70] and (long pair) LP…π interaction in the TS5RR (RR-configured transition state), which is due to the long distance between the -CF₃ substituent and NHC catalyst in the RR-configuration. This is why TS5SS is more stable than TS5RR. While the -CF₃ substituent is replaced by the small -F group, although there is still not C-H…F interaction, the C-H…O hydrogen bond interactions between the substrate and NHC catalyst in TS5RR

′

become significantly stronger than those of C-H…O and C-H…F hydrogen bond interactions in transition state TS5SS

′

, which is the key factor in strengthening the stability of the RR-configured transition state TS5RR

′

and leads to the switchable stereoselectivity for the reaction. Noteworthily, 20 possible conformations for TS5SS, TS5RR, TS5SS

′

, and TS5RR

′

were proposed and optimized to ensure that the conformation with the lowest energy was selected. The calculated results were provided in Figure S1 of the SI.

To show the practical value of the resulting enantioenriched fluorinated and fluoromethylated molecules, their antibacterial activities were initially examined by using Xanthomonas oryzae, Xanthomonas axonopodis, and Ralstonia solanacearum as target bacteria [71–73]. These bacteria are widespread plant pathogens that can cause serious plant diseases and huge economic losses in agricultural production [74]. Some of the chiral organofluorines from the current study exhibited superior antibacterial activities, as shown in Table 2. For example, compounds 10a and 8b showed higher inhibitory rates against Xoo than the commercial bacteriocide bismerthiazol when used at 50 μg/mL. Similarly, compounds 6b and 16 showed inhibitory rates against Xal that were similar to thiodiazole-copper. Under the same conditions, compounds 12 and 15a showed better inhibitory rates against Rs than thiodiazole-copper. These promising results indicated that the organofluorines produced in the current study have potential use as agrochemicals.

3. Discussion

Less

In summary, asymmetric desymmetrization of a novel prochiral 1,3-diketone with a fluorine or fluorinated methyl group has been demonstrated under NHC organocatalysis. Accordingly, a versatile and practical strategy for the construction of diverse organofluorines featuring fluorine or fluoromethyl groups (CF₃, CF₂H, or CH₂F) has been successfully developed by the current strategy. Notably, products featuring five stereogenic centers, including three quaternary centers and two rings, have been efficiently constructed in this transformation. Mechanism studies and DFT calculations demonstrated that the first C-C bond formation is the stereoselectivity-determining step as well as C-H…O and C-H…F interactions are the key factors to control and even switch the enantioselectivity of the reaction by exchanging the fluoromethyl substituents. The initial test indicated that some of the obtained enantioenriched organofluorines showed competitive antibacterial activities. Further investigations and exploration of this catalytic process and the resulting enantioenriched organofluorines are underway in our laboratory.

4. Materials and Methods

Less

4.1. General Procedure for the Synthesis of Organofluorine 3

To an oven-dried screw-capped test tube equipped with a magnetic stir bar, the prochiral 1,3-diketones 1 (0.1 mmol), 2-bromoenals 2 (0.12 mmol), triazolium salt NHC B (5.0 mg, 10 mol %), NaOAc (12.3 mg, 1.5 equiv), and 4 Å MS (50 mg) were added. To this mixture was added anhydrous mesitylene (0.1 M). After completion of the reaction, purification of the crude residue gave the desired product 3.

Funding

Less

Nanjing Tech University
Natural Science Foundation of Jiangsu Province(BK20171460)
National Natural Science Foundation of China(21602105)
National Key R&D Program of China(2017YFA0204704)

References

Less

Borissov

, Davies

T. Q.

, Ellis

S. R.

, Fleming

T. A.

, Richardson

M. S. W.

, and Dixon

D. J.

, “Organocatalytic enantioselective desymmetrisation,” Chemical Society Reviews, vol. 45, no. 20, pp. 5474–5540, 2016

Zeng

X.-P.

, Cao

Z.-Y.

, Wang

Y.-H.

, Zhou

, and Zhou

, “Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters,” Chemical Reviews, vol. 116, no. 12, pp. 7330–7396, 2016

Das

, “Desymmetrization of cyclopentene-1,3-diones via alkylation, arylation, amidation and cycloaddition reactions,” ChemistrySelect, vol. 5, no. 45, pp. 14484–14509, 2020

Shu

, and Cossy

, “Asymmetric desymmetrization of alkene-, alkyne- and allene-tethered cyclohexadienones using transition metal catalysis,” Chemical Society Reviews, vol. 50, no. 1, pp. 658–666, 2021

Bocknack

B. M.

, Wang

L.-C.

, and Krische

M. J.

, “Desymmetrization of enone-diones via rhodium-catalyzed diastereo- and enantioselective tandem conjugate addition-aldol cyclization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 15, pp. 5421–5424, 2004

Wadamoto

, Phillips

E. M.

, Reynolds

T. E.

, and Scheidt

K. A.

, “Enantioselective synthesis of α,α-disubstituted cyclopentenes by anN-Heterocyclic carbene-catalyzed desymmetrization of 1,3-diketones,” Journal of the American Chemical Society, vol. 129, no. 33, pp. 10098–10099, 2007

Partridge

B. M.

, Solana González

, and Lam

H. W.

, “Iridium-catalyzed arylative cyclization of alkynones by 1,4-iridium migration,” Angewandte Chemie International Edition, vol. 53, no. 25, pp. 6523–6527, 2014

, Chen

, Bai

Y.-B.

, and Dong

V. M.

, “Diastereodivergent construction of bicyclic γ-lactones via enantioselective ketone hydroacylation,” Journal of the American Chemical Society, vol. 138, no. 37, pp. 12013–12016, 2016

Zhu

, Wang

, Zhao

, Sun

W.-Y.

, and Shi

, “Enantioselective palladium-catalyzed intramolecular α-arylative desymmetrization of 1,3-diketones,” Journal of the American Chemical Society, vol. 139, no. 46, pp. 16486–16489, 2017

Cuadros

, Dell'Amico

, and Melchiorre

, “Forging fluorine-containing quaternary stereocenters by a light-driven organocatalytic aldol desymmetrization process,” Angewandte Chemie International Edition, vol. 56, no. 39, pp. 11875–11879, 2017

Cai

, Zhang

, Chen

, Lepage

R. J.

, Houk

K. N.

, Krenske

E. H.

, and Kwon

, “Catalytic asymmetric Staudinger-azaWittig reaction for the synthesis of heterocyclic amines,” Journal of the American Chemical Society, vol. 141, no. 24, pp. 9537–9542, 2019

Chen

, Zhang

, Maria-Solano

M. A.

, Liu

, Li

, Feng

, Liu

, Osuna

, Guo

R.-T.

, Wu

, Zhu

, and Ma

, “Efficient reductive desymmetrization of bulky 1,3-cyclodiketones enabled by structure-guided directed evolution of a carbonyl reductase,” Nature Catalysis, vol. 2, no. 10, pp. 931–941, 2019

Gong

, Wen

, and Zhang

, “Desymmetrization of cyclic 1,3-diketonesviaIr-catalyzed hydrogenation: an efficient approach to cyclic hydroxy ketones with a chiral quaternary carbon,” Chemical Science, vol. 10, no. 25, pp. 6350–6353, 2019

C.-B.

, Song

, Chen

M.-W.

, Shen

H.-Q.

, and Zhou

Y.-G.

, “Construction of multiple-substituted chiral cyclohexanes through hydrogenative desymmetrization of 2,2,5-trisubstituted 1,3-cyclohexanediones,” Organic Letters, vol. 21, no. 23, pp. 9401–9404, 2019

Zhu

, Liu

, Smetankova

, Zhuo

, Mou

, Chai

, Jin

, and Chi

Y. R.

, “Carbene‐catalyzed desymmetrization and direct construction of arenes with all‐carbon quaternary chiral center,” Angewandte Chemie International Edition, vol. 58, no. 44, pp. 15778–15782, 2019

Zanghi

J. M.

, Liu

, and Meek

S. J.

, “Enantio- and diastereoselective synthesis of functionalized carbocycles by Cucatalyzed borylative cyclization of alkynes with ketones,” Organic Letters, vol. 21, no. 13, pp. 5172–5177, 2019

Chen

, Wang

, Ding

, and Kong

, “Synthesis of bridged tricyclo[5.2.1.0^1,5]decanes via nickel-catalyzed asymmetric domino cyclization of enynones,” Nature Communications, vol. 11, no. 1, pp. 1882–1890, 2020

Ding

Y.-X.

, Zhu

Z.-H.

, Wang

, Yu

C.-B.

, and Zhou

Y.-G.

, “Construction of three stereocenters via hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones,” Science China: Chemistry, vol. 64, no. 2, pp. 232–237, 2021

Yang

, Dai

, Luo

, Lau

K. K.

, Lan

, Shao

, and Zhao

, “Desymmetrization of 1,3-diones by catalytic enantioselective condensation with hydrazine,” Journal of the American Chemical Society, vol. 143, no. 11, pp. 4179–4186, 2021

Qin

X.-L.

, Li

, and Han

F.-S.

, “Desymmetric enantioselective reduction of cyclic 1,3-diketones catalyzed by a recyclableP-chiral phosphinamide organocatalyst,” Journal of the American Chemical Society, vol. 143, no. 7, pp. 2994–3002, 2021

Ghosh

, Balhara

, Jindal

, and Mukherjee

, “Catalytic enantioselective desymmetrizing Fischer indolization through dynamic kinetic resolution,” Angewandte Chemie International Edition, vol. 60, no. 16, pp. 9086–9092, 2021

Prévost

, Dupré

, Leutzsch

, Wang

, Wakchaure

, and List

, “Catalytic asymmetric Torgov cyclization: a concise total synthesis of (+)-estrone,” Angewandte Chemie International Edition, vol. 53, no. 33, pp. 8770–8773, 2014

Wang

, Feng

, Tang

, and Jiang

, “Recent advances of desymmetrization protocol applied in natural product total synthesis,” Tetrahedron Letters, vol. 55, no. 52, pp. 7147–7155, 2014

Kirsch

Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2013

Muller

, Faeh

, and Diederich

, “Fluorine in pharmaceuticals: looking beyond intuition,” Science, vol. 317, no. 5846, pp. 1881–1886, 2007

Purser

, Moore

P. R.

, Swallow

, and Gouverneur

, “Fluorine in medicinal chemistry,” Chemical Society Reviews, vol. 37, no. 2, pp. 320–330, 2008

Wang

, Sánchez-Roselló

, Aceña

J. L.

, Del Pozo

, Sorochinsky

A. E.

, Fustero

, Soloshonok

V. A.

, and Liu

, “Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011),” Chemical Reviews, vol. 114, no. 4, pp. 2432–2506, 2014

Huchet

Q. A.

, Kuhn

, Wagner

, Kratochwil

N. A.

, Fischer

, Kansy

, Zimmerli

, Carreira

E. M.

, and Müller

, “Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery,” Journal of Medicinal Chemistry, vol. 58, no. 22, pp. 9041–9060, 2015

Gillis

E. P.

, Eastman

K. J.

, Hill

M. D.

, Donnelly

D. J.

, and Meanwell

N. A.

, “Applications of fluorine in medicinal chemistry,” Journal of Medicinal Chemistry, vol. 58, no. 21, pp. 8315–8359, 2015

Fried

, and Sabo

E. F.

, “9α-Fluoro derivatives of cortisone and hydrocortisone,” Journal of the American Chemical Society, vol. 76, no. 5, pp. 1455–1456, 1954

O’Hagan

, and Harper

D. B.

, “Fluorine-containing natural products,” Journal of Fluorine Chemistry, vol. 100, no. 1-2, pp. 127–133, 1999

Furuya

, Kamlet

A. S.

, and Ritter

, “Catalysis for fluorination and trifluoromethylation,” Nature, vol. 473, no. 7348, pp. 470–477, 2011

Gouverneur

, and Seppelt

, “Introduction: fluorine chemistry,” Chemical Reviews, vol. 115, no. 2, pp. 563–565, 2015

Yang

X. Y.

, Wu

, Phipps

R. J.

, and Toste

F. D.

, “Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions,” Chemical Reviews, vol. 115, no. 2, pp. 826–870, 2015

Groult

, Leroux

, and Tressaud

Modern Synthesis Processes and Reactivity of Fluorinated Compounds, Academic Press, London, 2017

Zhu

, Han

, Wang

, Shibata

, Sodeoka

, Soloshonok

V. A.

, Coelho

J. A. S.

, and Toste

F. D.

, “Modern approaches for asymmetric construction of carbon-fluorine quaternary stereogenic centers: synthetic challenges and pharmaceutical needs,” Chemical Reviews, vol. 118, no. 7, pp. 3887–3964, 2018

Shibata

, Matsnev

, and Cahard

, “Shelf-stable electrophilic trifluoromethylating reagents: a brief historical perspective,” Beilstein Journal of Organic Chemistry, vol. 6, p. 65, 2010

Champagne

P. A.

, Desroches

, Hamel

J.-D.

, Vandamme

, and Paquin

J.-F.

, “Monofluorination of organic compounds: 10 years of innovation,” Chemical Reviews, vol. 115, no. 17, pp. 9073–9174, 2015

, Hu

, and Hu

, “Good partnership between sulfur and fluorine: sulfur-based fluorination and fluoroalkylation reagents for organic synthesis,” Chemical Reviews, vol. 115, no. 2, pp. 765–825, 2015

Charpentier

, Früh

, and Togni

, “Electrophilic trifluoromethylation by use of hypervalent iodine reagents,” Chemical Reviews, vol. 115, no. 2, pp. 650–682, 2015

Kalim

, Duhail

, Le

T.-N.

, Vanthuyne

, Anselmi

, Togni

, and Magnier

, “Merging hypervalent iodine and sulfoximine chemistry: a new electrophilic trifluoromethylation reagent,” Chemical Science, vol. 10, no. 45, pp. 10516–10523, 2019

, Xue

X.-S.

, and Cheng

J.-P.

, “Establishing cation and radical donor ability scales of electrophilic F, CF₃, and SCF3transfer reagents,” Accounts of Chemical Research, vol. 53, no. 1, pp. 182–197, 2020

Enders

, Niemeier

, and Henseler

, “Organocatalysis by N-heterocyclic carbenes,” Chemical Reviews, vol. 107, no. 12, pp. 5606–5655, 2007

Bugaut

, and Glorius

, “Organocatalytic umpolung: N-heterocyclic carbenes and beyond,” Chemical Society Reviews, vol. 41, no. 9, pp. 3511–3522, 2012

Cohen

D. T.

, and Scheidt

K. A.

, “Cooperative Lewis acid/N-heterocyclic carbene catalysis,” Chemical Science, vol. 3, no. 1, pp. 53–57, 2012

De Sarkar

, Biswas

, Samanta

R. C.

, and Studer

, “Catalysis with N-heterocyclic carbenes under oxidative conditions,” Chemistry - A European Journal, vol. 19, no. 15, pp. 4664–4678, 2013

Ryan

S. J.

, Candish

, and Lupton

D. W.

, “Acyl anion free N-heterocyclic carbene organocatalysis,” Chemical Society Reviews, vol. 42, no. 12, pp. 4906–4917, 2013

Hopkinson

M. N.

, Richter

, Schedler

, and Glorius

, “An overview of N-heterocyclic carbenes,” Nature, vol. 510, no. 7506, pp. 485–496, 2014

Flanigan

D. M.

, Romanov-Michailidis

, White

N. A.

, and Rovis

, “Organocatalytic reactions enabled by N-heterocyclic carbenes,” Chemical Reviews, vol. 115, no. 17, pp. 9307–9387, 2015

Chen

X. Y.

, Gao

Z. H.

, and Ye

, “Bifunctional N-heterocyclic carbenes derived from L-pyroglutamic acid and their applications in enantioselective organocatalysis,” Accounts of Chemical Research, vol. 53, no. 3, pp. 690–702, 2020

Ohmiya

, “N-Heterocyclic carbene-based catalysis enabling cross-coupling reactions,” ACS Catalysis, vol. 10, no. 12, pp. 6862–6869, 2020

Chen

, Wang

, Jin

, and Chi

Y. R.

, “N‐Heterocycliccarbene organocatalysis: activation modes and typical reactive intermediates,” Chinese Journal of Chemistry, vol. 38, no. 10, pp. 1167–1202, 2020

Zhang

, Huang

, Guo

, Li

, Fu

, and Huang

, “Access to enantioenriched organosilanes from enals and β-silyl enones: carbene organocatalysis,” Angewandte Chemie, International Edition, vol. 57, no. 17, pp. 4594–4598, 2018

Gao

, Liu

, Fu

, and Huang

, “Facile synthesis of 2,2-diacyl spirocyclohexanones via an N-heterocyclic carbene-catalyzed formal [3C + 3C] annulation,” Organic Letters, vol. 21, no. 4, pp. 926–930, 2019

Wang

, Shi

, Hu

, Chen

, Guo

, Hu

, Gong

, Guo

, Wei

, Fu

, and Huang

, “Organocatalytic asymmetric _N_ -sulfonyl amide C-N bond activation to access axially chiral biaryl amino acids,” Nature Communications, vol. 11, no. 1, p. 946, 2020

Zhang

, Huang

, Guo

, Wei

, Gong

, and Fu

, “Carbene-catalyzed enantioselective synthesis of γ-keto-β-silyl esters and amides,” Organic Letters, vol. 22, no. 24, pp. 9545–9550, 2020

Wang

, Zhang

Q.-C.

, Wei

, Zhang

, Huang

, Wei

, Fu

, and Huang

, “Asymmetric carbene-catalyzed oxidation of functionalized aldimines as 1,4-dipoles,” Angewandte Chemie, International Edition, vol. 60, no. 14, pp. 7913–7919, 2021

Ding

, Meazza

, Guo

, Yang

J. W.

, and Rios

, “New development in the enantioselective synthesis of spiro compounds,” Chemical Society Reviews, vol. 47, no. 15, pp. 5946–5996, 2018

P.-W.

, Yu

J.-S.

, Chen

, Cao

Z.-Y.

, Zhou

, and Zhou

, “Catalytic enantioselective construction of spiro quaternary carbon stereocenters,” ACS Catalysis, vol. 9, no. 3, pp. 1820–1882, 2019

Recent advances in asymmetric organocatalytic construction of 3,3

′

-spirocyclic oxindoles

Hong

, and Wang

, “Recent advances in asymmetric organocatalytic construction of 3,3′-spirocyclic oxindoles,” Advanced Synthesis & Catalysis, vol. 355, no. 6, pp. 1023–1052, 2013

Cheng

, Ishihara

, Tan

, and Barbas C. F. III, “Organocatalytic asymmetric assembly reactions: synthesis of spirooxindoles via organocascade strategies,” ACS Catalysis, vol. 4, no. 3, pp. 743–762, 2014

, Yu

D.-Q.

, and Liu

H.-M.

, “Spirooxindoles: promising scaffolds for anticancer agents,” European Journal of Medicinal Chemistry, vol. 97, pp. 673–698, 2015

Mahatthananchai

, and Bode

J. W.

, “On the mechanism of N-heterocyclic carbene-catalyzed reactions involving acyl azoliums,” Accounts of Chemical Research, vol. 47, no. 2, pp. 696–707, 2014

Mondal

, Yetra

S. R.

, Mukherjee

, and Biju

A. T.

, “NHC-catalyzed generation of α,β-unsaturated acylazoliums for the enantioselective synthesis of heterocycles and carbocycles,” Accounts of Chemical Research, vol. 52, no. 2, pp. 425–436, 2019

Ghosh

, and Biju

A. T.

, “Revealing the similarities of α,β-unsaturated iminiums and acylazoliums in organocatalysis,” Angewandte Chemie International Edition, vol. 60, no. 25, pp. 13712–13724, 2021

Shee

, Mukherjee

, Gonnade

R. G.

, and Biju

A. T.

, “Enantioselective synthesis of tricyclic β-lactones by NHC-catalyzed desymmetrization of cyclic 1,3-diketones,” Organic Letters, vol. 22, no. 14, pp. 5407–5411, 2020

J.-A.

, and Cahard

, “Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions,” Chemical Reviews, vol. 104, no. 12, pp. 6119–6146, 2004

Feng

, Xiao

Y.-L.

, and Zhang

, “Transition-metal (Cu, Pd, Ni)-catalyzed difluoroalkylation via cross-coupling with difluoroalkyl halides,” Accounts of Chemical Research, vol. 51, no. 9, pp. 2264–2278, 2018

X.-S.

, Yu

J.-S.

, and Zhou

, “Catalytic selective mono- and difluoroalkylation using fluorinated silyl enol ethers,” Chemical Communications, vol. 55, no. 91, pp. 13638–13648, 2019

Hao

Y.-J.

, Yu

J. S.

, Zhou

, Wang

, and Zhou

, “Influence of C-F…H-X interactions on organic reactions,” Acta Chimica Sinica, vol. 76, no. 12, pp. 925–939, 2018

Gottwald

T. R.

, Hughes

, Graham

J. H.

, Sun

, and Riley

, “The citrus canker epidemic in Florida: the scientific basis of regulatory eradication policy for an invasive species,” Phytopathology, vol. 91, no. 1, pp. 30–34, 2001

, Hu

, Xie

, Chen

, Jin

, and Song

, “Design, synthesis, and evaluation of new sulfone derivatives containing a 1,3,4-oxadiazole moiety as active antibacterial agents,” Journal of Agricultural and Food Chemistry, vol. 66, no. 12, pp. 3093–3100, 2018

Wang

P. Y.

, Wang

M. W.

, Zeng

, Xiang

, Rao

J. R.

, Liu

Q. Q.

, Liu

L. W.

, Wu

Z. B.

, Li

, Song

B. A.

, and Yang

, “Rational optimization and action mechanism of novel imidazole (or imidazolium)-labeled 1,3,4-oxadiazole thioethers as promising antibacterial agents against plant bacterial diseases,” Journal of Agricultural and Food Chemistry, vol. 67, no. 13, pp. 3535–3545, 2019

Dang

Q. L.

, Kim

W. K.

, Nguyen

C. M.

, Choi

Y. H.

, Choi

G. J.

, Jang

K. S.

, Park

M. S.

, Lim

C. H.

, Luu

N. H.

, and Kim

J. C.

, “Nematicidal and antifungal activities of Annonaceous acetogenins fromAnnona squamosaagainst various plant pathogens,” Journal of Agricultural and Food Chemistry, vol. 59, no. 20, pp. 11160–11167, 2011

Appendix

Less

Year 2021 volume 2021 Issue 8

PDF

113

Cite this Article

BibTeX

Article Info

doi: 10.34133/2021/9867915

Receive Date：2021-05-26
Online Date：2026-10-27
Published：2021-08-20

Article Data

Affiliations

History

Received：2021-05-26
Accepted：2021-07-15

Funding

Nanjing Tech University

Natural Science Foundation of Jiangsu Province(BK20171460)

National Natural Science Foundation of China(21602105)

National Key R&D Program of China(2017YFA0204704)

Affiliations

¹Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM) Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, China

²College of Chemistry and Green Catalysis Center, Zhengzhou University, Zhengzhou, Henan 450001, China

³School of Chemistry and Molecular Engineering, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, China

⁵Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore, Singapore, 637371

References

Share

https://castjournals.cast.org.cn/joweb/research/EN/10.34133/2021/9867915

Share to

Scan QR to access full text

Cite this article

BibTeX

Citations

表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT

Table 1 Optimized conditions^[a].


Entry^[a]	NHC·HX	Base	Solvent	Yield (%)^[b]	dr^[c]	ee^[d]
1	A	K₂CO₃	Toluene	11	—	—
2	A	Cs₂CO₃	Toluene	<10	—	—
3	A	Na₂CO₃	Toluene	<10	—	—
4	A	NaHCO₃	Toluene	<10	—	—
5	A	DBU	Toluene	<10	—	—
6	A	KOAc	Toluene	80	>20 : 1	>99
7	A	NaOAc	Toluene	82	>20 : 1	>99
8	A	Et₃N	Toluene	19	—	—
9	B	NaOAc	Toluene	88	>20 : 1	>99
10	C	NaOAc	Toluene	84	>20 : 1	>99
11	D	NaOAc	Toluene	81	>20 : 1	98
12	E	NaOAc	Toluene	80	>20 : 1	89
13	B	NaOAc	DCM	81	>20 : 1	>99
14	B	NaOAc	THF	<10	—	—
15	B	NaOAc	Mesitylene	93	>20 : 1	>99
16	B	NaOAc	o-Xylene	90	>20 : 1	>99
17^[e]	B	NaOAc	Mesitylene	78	>20 : 1	>99

^[a]Standard condition: 1a (0.1 mmol), 2a (1.2 equiv), NHC·HX (10 mol%), solvent (0.1 M), 30°C, 24 h. ^[b]Yield of the product after column chromatography. ^[c]Determined via ¹H NMR spectroscopy. ^[d]Determined by chiral HPLC,

% ee = R ‐ S / R + S ∗ 100

. ^[e]5 mol% catalyst, 60 h.

Table 2 The antibacterial activity of the products.

Compound	Xanthomonas oryzae pv. oryzae (Xoo) inhibition rate 50 ppm	Xanthomonas axonopodis pv. citri (Xal) inhibition rate 50 ppm	Ralstonia solanacearum (Rs) inhibition rate 50 ppm
3a	$0.00 % ± 9.86 %$	$44.30 % ± 3.66 %$	$0.00 % ± 4.53 %$
6b	$74.71 % ± 10.22 %$	$73.14 % ± 6.77 %$	$78.26 % ± 4.53 %$
8b	$99.69 % ± 7.57 %$	$64.75 % ± 3.60 %$	$38.90 % ± 13.88 %$
10a	$93.40 % ± 21.20 %$	$41.87 % ± 4.98 %$	$58.95 % ± 4.70 %$
11	$21.46 % ± 1.91 %$	$35.69 % ± 11.07 %$	$47.03 % ± 6.87 %$
12	$0.00 % ± 19.67 %$	$41.28 % ± 2.90 %$	$94.57 % ± 0.55 %$
15a	$3.90 % ± 0.11 %$	$41.65 % ± 6.29 %$	$99.69 % ± 18.24 %$
16	$0.00 % ± 5.79 %$	$70.42 % ± 12.69 %$	$0.00 % ± 5.57 %$
Thiodiazole-copper	$89.29 % ± 10.69 %$	$79.32 % ± 0.64 %$	$93.29 % ± 1.19 %$
Bismerthiazol	$94.39 % ± 22.58 %$	$54.67 % ± 1.22 %$	$47.40 % ± 7.43 %$

Figure 1 Asymmetric desymmetrization of cyclic 1,3-diketone with fluorine functionalized groups: (a) our design on introducing fluorine or fluorinated substituents into symmetric 1,3-diketones; (b) this work: NHC-catalyzed asymmetric desymmetrization of fluorine functionalized 1,3-diketones; (c) biologically active molecules with multiple stereogenic centers containing fluorine-containing quaternary stereocenter; (d) naturally occurring and biologically active spirocyclohexane oxindoles.

Figure 2 Scope of reactions.

Figure 3 Scope of reactions.

Figure 4 Scope of reactions. Reaction conditions: 9 (0.1 mmol), 2 (1.2 mmol), NHC·HBF₄ B (2 mol%), NaOAc (1.5 mmol), mesitylene (1 mL), 4 Å MS (50 mg), 30°C, 24 h.

Figure 5 Synthetic application: (a) gram scale synthesis; (b) one pot process to enantioenriched spirocyclohexene product; (c) synthesis of enantioenriched trifluoromethylthiolated spirocyclohexene product; (d) one pot process to cycle-open product; (e) Baeyer-Villiger oxidation of the enantioenriched product.

Figure 6 Gibbs free energy profile of the entire catalytic cycle computed at the M06-2X/6-31G(d, p)/IEFPCM mesitylene level.

Figure 7 (a) The Gibbs free energy barrier differences ( $Δ Δ G ≠$ , energy in kcal/mol), (b) AIM analyses for transition states TS5SS, TS5RR, TS5SS $′$ , and TS5RR $′$ with different substitutes (distance in Å), and (c) summary of the values of Laplacian electron density ( $∇ 2 ρ$ in eÅ^-3).

Articles: Latest Articles; Most Read; Collections

Updates: Events; News; Multimedia

About: About Us

Contact

No. 86 Xueyuan South Road, Haidian District, Beijing

100081

010-62662699(Operation and Technical Support)

qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House