Download PDF
Short Communication  |  Open Access  |  18 Jul 2023

Direct construction of d3-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization

Views: 506 |  Downloads: 201 |  Cited:  1
Chem Synth 2023;3:34.
10.20517/cs.2023.04 |  © The Author(s) 2023.
Author Information
Article Notes
Cite This Article

Abstract

The construction of d3-methylated all-carbon quaternary stereocenters has been successfully developed via carbene-catalyzed desymmetrization of prochiral d3-methylated oxindolyl 1,3-diketones. Three new stereogenic centers were efficiently constructed with satisfactory outcomes. Diverse spiro-polycyclic molecules with a d3-methylated all-carbon quaternary stereocenter were generated in good to excellent yields with good to excellent diastereoselectivities and excellent enantioselectivities. This reaction features a broad substrate scope, good functional-group tolerance, and easy scale-up.

Keywords

d3-Methylated, all-carbon quaternary stereocenters, N-Heterocyclic carbene, organocatalysis, desymmetrization

As a result of the unique nature of deuterium, deuterium-labeled organic compounds have been widely used in organic chemistry[1,2], pharmaceuticals[3-5], and materials[6-10]. In the field of medicinal chemistry, replacing a hydrogen atom of a bioactive molecule with a deuterium atom can significantly improve the pharmacokinetics, biological activities, and stability of chemically unstable stereoisomers while also reducing toxicities[11-14]. Furthermore, due to the well-known “magic methyl effect”[15-18], the synthesis and application of d3-methylated organic molecules have received continuous interest. And several d3-methylated organic molecules have become marketed drugs or are currently undergoing clinical trials [Figure 1]. For example, Austedo, with two CD3 groups, as the first deuterated drug, is applied in the treatment of symptoms of Huntington’s disease[19,20]. Donafenib, as an orally available multikinase inhibitor, was approved by the NMPA in 2021 for treating liver cancer[21]. CTP-518 (d15-Atazanavir) displays an average 52% increase in half-life compared to atazanavir[22]. CTP-499 (d5-Pentoxifylline) exhibits antifibrogenic, antioxidative, and anti-inflammatory activities, with higher plasma concentrations and related major metabolites compared to regular Pentoxifylline[23,24]. Despite these advancements, the asymmetric construction of chiral organic molecules with d3-methylated all-carbon quaternary stereocenters remains underdeveloped. However, methylated all-carbon quaternary stereocenters have been widespread in natural products and biological molecules, offering a diverse set of promising biological activities[25].

Direct construction of <i>d</i><sub><i>3</i></sub>-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization

Figure 1. Asymmetric desymmetrization of d3-methylated cyclic 1,3-diketones; (a) Representative examples containing CD3; (b) Naturally occurring and biologically active molecules with methylated all-carbon quaternary stereocenters; (c) This work: NHC-catalyzed asymmetric desymmetrization of d3-methylated 1,3-diketones.

N-heterocyclic carbene (NHC) catalysis, as one of the most efficient methods of asymmetric catalysis, has been widely used in the construction of diverse chiral molecules[26-39]. Among them, carbene-catalyzed desymmetrization of 1,3-diketones has been recognized as one of the most powerful strategies for the construction of chiral centers, especially chiral all-carbon quaternary centers[40-47]. Although NHC catalysis has shown potential applications in the construction of deuterated organic molecules[48-51], the application of NHC catalysis to construct chiral deuterated organic molecules remains underdeveloped. As part of our ongoing interest in organocatalysis[51-56], we designed novel prochiral d3-methylated oxindolyl 1,3-diketones for the asymmetric construction of d3-methylated all-carbon quaternary stereocenters based on NHC-catalyzed asymmetric desymmetrization. These readily available prochiral d3-methylated oxindolyl 1,3-diketones could react with unsaturated acyl triazolium intermediates[57] obtained from bromoenals with NHC to construct spiro-polycyclic molecules with a d3-methylated all-carbon quaternary stereocenter with excellent outcomes. Notably, spirocyclic and oxindole moieties of the products are proven among the most important scaffolds in natural products and bioactive molecules[58-61].

The reaction of (Z)-2-bromo-3-phenylacrylaldehyde 2a and prochiral 2-(methyl-d3)-2-[(1-methyl-2-oxoindolin-3-yl)methyl]-1H-indene-1,3(2H)-dione 1a was initially selected to optimize reaction conditions. The key results are summarized in Figure 2. As expected, the desired chiral d3-methylated product 3a’ could be found when aminoindanol-derived triazolium precatalyst NHC A was used in the presence of K2CO3 in toluene at room temperature. Notably, due to unavoidable release of CO2 for product 3a’ during the reaction process and in the following purification step, one more decarbonation operation, adding SiO2 to the reaction system under 70 oC for 10 h, was further performed. Accordingly, the asymmetrical d3-methylated product 3a was generated smoothly in 70% yield with 3:1 dr and 80% ee (Entry 1) [Figure 2]. Subsequently, base screening showed that sodium acetate was the best base, leading to the formation of the product 3a in excellent yield (90%) with good diastereoselectivity (13:1 dr) and excellent enantioselectivity (95% ee) (Entries 2-4). Next, several NHC catalysts were examined (Entries 5-8). All selected NHC catalysts could promote reaction smoothly, with NHC precatalyst C bearing a NO2 substituent on the indane moiety proving to be the better choice to deliver the product 3a in both excellent yield (90%) with enantioselectivity (> 99% ee) and good diastereoselectivity (13:1 dr). Several solvents were then investigated to further improve the diastereoselectivity (Entries 9-14). The excellent diastereoselectivity (> 20:1) was realized with both excellent yield (95%) and enantioselectivity (> 99) by using mesitylene as the solvent (Entry 14). In the absence of the catalyst, no reaction occurred (Entry 15). The absolute configuration of products 3 was determined via X-ray structural analysis of 3 h.

Direct construction of <i>d</i><sub><i>3</i></sub>-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization

Figure 2. Optimized conditions[a]. [a] Standard condition: 1a (0.1 mmol), 2a (1.2 equiv), NHC.HX (10 mol%), solvent (0.1 M), 30 °C, and 24 h, then SiO2, 70 °C, and 10 h; [b] Yield of the product 3a after column chromatography; [c] Determined via 1H NMR spectroscopy; [d] Determined by chiral HPLC, % ee = (R-S) / (R + S) * 100.

After successfully establishing the optimal conditions, the substrate scope of this desymmetrization strategy for enals was then evaluated by using 1a as a model substrate [Figure 3]. For bromoenals with aromatic rings bearing electron-donating groups (such as Me, MeO) or electron-withdrawing groups (such as F, Cl, Br, and NO2), all the reactions proceeded smoothly to form the d3-methylated products 3b-i in excellent yields (90%-94%) with good to excellent diastereoselectivities (16:1 dr-> 20:1 dr values) and excellent enantioselectivities (> 99% ee values for all the cases).

Direct construction of <i>d</i><sub><i>3</i></sub>-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization

Figure 3. Scope of Reactions.

Bromoenals bearing naphthalene or heteroaromatic rings (2-furyl and 2-thienyl) did not influence the efficiency, affording the corresponding d3-methylated products 3j-l with good to excellent outcomes (90%-97% yields, 11:1-> 20:1 dr values and > 99% values for all the cases). Subsequently, the generation of trideuteromethyl oxindolyl 1,3-diketones 2 was evaluated. For trideuteromethyl oxindolyl 1,3-diketones, several substituents at the 4-, 5-, 6-, and 7-positons on the oxindole ring were also compatible with the reaction to generate the d3-methylated products 3m-3q in excellent yields (94%-97%) with good to excellent diastereoselectivities (10:1-> 20:1 dr values) and excellent enantioselectivities (> 99% ee values). Substrates with N-benzyl and N-allyl groups reacted efficiently to form d3-methylated products 3r and 3s in 94% and 87% yields with 17:1 dr, > 20:1 dr values and > 99%, 96% ee values, respectively. Unfortunately, β-alkyl-substituted enals failed to deliver the product in our reaction.

After successfully documenting the synthesis of trideuteromethyl molecules with three stereogenic centers under NHC organocatalysis, to further evaluate the scope and limitations of this strategy, other alkyl groups were introduced into the prochiral substrates [Figure 4]. The CD3 group can be replaced with a methyl group, with the corresponding product 4a formed in 96% yield with 13:1 dr and > 99% ee. Compound 1 with a propyl group also works efficiently to result in the product 4b in 87% yields with > 20:1 dr and > 99% ee. Notably, the substrates with functional groups, such as allyl, propargyl, and NO2 substituted benzyl and acetylethoxy groups, were also compatible with this transformation, resulting in the formation of products 4c-f in excellent yields (90%-97%) with excellent diastereoselectivities (> 20:1 dr values) and enantioselectivities (> 99% ee values).

Direct construction of <i>d</i><sub><i>3</i></sub>-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization

Figure 4. Scope of reactions. The reaction conditions are the same in Figure 2, Entry 14.

To show the practicality of our method, a gram-scale reaction was carried out [Figure 5]. Pleasingly, with the use of 1.0 gram of prochiral substrate 2a under the standard conditions, the reaction worked efficiently to afford 1.23 grams of the product 3a (97% yield) without any erosion of dr value and ee value.

Direct construction of <i>d</i><sub><i>3</i></sub>-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization

Figure 5. Gram-scale synthesis.

To show further potential applications of this method, the synthetic transformation was performed, as shown in Figure 6. One-pot ring-opening of intermediate 3a’ could give the molecules five stereogenic centers. Treatment of intermediate 3a’ with nucleophiles such as methanol, benzyl mercaptan, and benzylamine at room temperature led to the formation of ring-opening products 5-7 in good yields and without any erosion of dr values and ee values.

Direct construction of <i>d</i><sub><i>3</i></sub>-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization

Figure 6. One pot process to ring-opening products.

On the basis of previous reports and current results[46], a plausible mechanism is depicted in Figure 7. The process begins with the addition of carbene to bromoenal 1a, followed by debromination to give α, β-unsaturated acyl azolium I. Deprotonation of trideuteromethyl oxindolyl 1,3-diketones 2a results in the formation of intermediate II, which undergoes Michael addition to intermediate I to form intermediate III. Then, intramolecular cyclization of intermediate III could generate intermediate IV, which undergoes intramolecular lactonization to give 3a’ and regenerate free carbene. Subsequently, treatment of 3a’ with acidic SiO2 affords the final product 3a via a decarbonation process.

Direct construction of <i>d</i><sub><i>3</i></sub>-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization

Figure 7. Proposed mechanism.

In summary, we have successfully established an efficient strategy for the asymmetric construction of spiro-polycyclic molecules with a d3-methylated all-carbon quaternary stereocenter under carbene organocatalysis. This versatile and practical asymmetric desymmetrization features a broad substrate scope, good functional-group tolerance, and can be easily scaled-up. Notably, this strategy enables the efficient construction of three stereogenic centers, including two quaternary centers. Further investigations and explorations of this catalytic process and the resulting enantioenriched d3-methylated molecules are currently underway in our laboratory.

DECLARATIONS

Authors’ contributions

Designing the experiments, writing the manuscript, and being responsible for the whole work: Fu Z, Zhang X

Performing the experiments: Guo J, Zhang Y

Synthesizing the substrates: Guo J, Zhang Y

Availability of data and materials

Detailed experimental procedures and spectroscopic data were published as Supplementary Materials in the journal.

Financial support and sponsorship

We acknowledge the financial support by the Ningbo Natural Science Foundation (202003N4063) and the General Program of Chongqing Natural Science Foundation Project (cstc2020jcyj-msxmX0712).

Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Copyright

© The Author(s) 2023.

Supplementary Materials

REFERENCES

1. Sun Q, Soulé JF. Broadening of horizons in the synthesis of CD3-labeled molecules. Chem Soc Rev 2021;50:10806-35.

2. Kopf S, Bourriquen F, Li W, Neumann H, Junge K, Beller M. Recent developments for the deuterium and tritium labeling of organic molecules. Chem Rev 2022;122:6634-718.

3. Atzrodt J, Derdau V, Kerr WJ, Reid M. Deuterium- and tritium-labelled compounds: applications in the life sciences. Angew Chem Int Ed Engl 2018;57:1758-84.

4. Pirali T, Serafini M, Cargnin S, Genazzani AA. Applications of deuterium in medicinal chemistry. J Med Chem 2019;62:5276-97.

5. Prakash G, Paul N, Oliver GA, Werz DB, Maiti D. C-H deuteration of organic compounds and potential drug candidates. Chem Soc Rev 2022;51:3123-63.

6. Wang P, Wang F, Chen Y, et al. Synthesis of all-deuterated tris(2-phenylpyridine) iridium for highly stable electrophosphorescence: the “deuterium effect”. J Mater Chem C 2013;1:4821.

7. Abe T, Miyazawa A, Konno H, Kawanishi Y. Deuteration isotope effect on nonradiative transition of fac-tris (2-phenylpyridinato) iridium (III) complexes. Chem Phys Lett 2010;491:199-202.

8. Box CL, Zhang Y, Yin R, Jiang B, Maurer RJ. Determining the effect of hot electron dissipation on molecular scattering experiments at metal surfaces. JACS Au 2021;1:164-73.

9. Bae HJ, Kim JS, Yakubovich A, et al. Protecting benzylic C-H bonds by deuteration doubles the operational lifetime of deep-blue Ir-Phenylimidazole dopants in phosphorescent oleds. Adv Opt Mater 2021;9:2100630.

10. Liu X, Chan C, Mathevet F, et al. Isotope effect of host material on device stability of thermally activated delayed fluorescence organic light-emitting diodes. Small Science 2021;1:2000057.

11. Cleland WW. The use of isotope effects to determine enzyme mechanisms. Arch Biochem Biophys 2005;433:2-12.

12. Shao L, Hewitt MC. The kinetic isotope effect in the search for deuterated drugs. Drug News Perspect 2010;23:398-404.

13. Gómez-Gallego M, Sierra MA. Kinetic isotope effects in the study of organometallic reaction mechanisms. Chem Rev 2011;111:4857-963.

14. Katsnelson A. Heavy drugs draw heavy interest from pharma backers. Nat Med 2013;19:656.

15. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science 2001;293:1068-70.

16. Barreiro EJ, Kümmerle AE, Fraga CA. The methylation effect in medicinal chemistry. Chem Rev 2011;111:5215-46.

17. Leung CS, Leung SS, Tirado-Rives J, Jorgensen WL. Methyl effects on protein-ligand binding. J Med Chem 2012;55:4489-500.

18. Zhang L, Ding X, Cui J, et al. Cysteine methylation disrupts ubiquitin-chain sensing in NF-κB activation. Nature 2011;481:204-8.

19. Schmidt C. First deuterated drug approved. Nat Biotechnol 2017;35:493-4.

20. Mullard A. FDA approves dupilumab for severe eczema. Nat Rev Drug Discov 2017;16:305.

21. Zhong L, Hou C, Zhang L, Zhao J, Li F, Li W. Synthesis of deuterium-enriched sorafenib derivatives and evaluation of their biological activities. Mol Divers 2019;23:341-50.

22. Barratt M J, Frail D E. Drug repositioning: bringing new life to shelved assets and existing drugs. Hoboken: John Wiley & Sons; 2012.

23. Braman V, Graham P, Cheng C, et al. A randomized phase I evaluation of CTP-499, a novel deuterium-containing drug candidate for diabetic nephropathy. Clin Pharmacol Drug Dev 2013;2:53-66.

24. Sabounjian L, Graham P, Wu L, et al. A first-in-patient, multicenter, double-blind, 2-arm, placebo-controlled, randomized safety and tolerability study of a novel oral drug candidate, CTP-499, in chronic kidney disease. Clin Pharmacol Drug Dev 2016;5:314-25.

25. Zeng XP, Cao ZY, Wang YH, Zhou F, Zhou J. Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters. Chem Rev 2016;116:7330-96.

26. Enders D, Niemeier O, Henseler A. Organocatalysis by N-heterocyclic carbenes. Chem Rev 2007;107:5606-55.

27. Bugaut X, Glorius F. Organocatalytic umpolung: N-heterocyclic carbenes and beyond. Chem Soc Rev 2012;41:3511-22.

28. Cohen DT, Scheidt KA. Cooperative lewis acid/N-heterocyclic carbene catalysis. Chem Sci 2012;3:53-7.

29. Sarkar S, Biswas A, Samanta RC, Studer A. Catalysis with N-heterocyclic carbenes under oxidative conditions. Chemistry 2013;19:4664-78.

30. Ryan SJ, Candish L, Lupton DW. Acyl anion free N-heterocyclic carbene organocatalysis. Chem Soc Rev 2013;42:4906-17.

31. Hopkinson MN, Richter C, Schedler M, Glorius F. An overview of N-heterocyclic carbenes. Nature 2014;510:485-96.

32. Flanigan DM, Romanov-Michailidis F, White NA, Rovis T. Organocatalytic reactions enabled by N-heterocyclic carbenes. Chem Rev 2015;115:9307-87.

33. Chen XY, Gao ZH, Ye S. Bifunctional N-Heterocyclic carbenes derived from l-pyroglutamic acid and their applications in enantioselective organocatalysis. Acc Chem Res 2020;53:690-702.

34. Ohmiya H. N-Heterocyclic carbene-based catalysis enabling cross-coupling reactions. ACS Catal 2020;10:6862-9.

35. Chen X, Wang H, Jin Z, Chi YR. N-Heterocyclic carbene organocatalysis: activation modes and typical reactive intermediates. Chin J Chem 2020;38:1167-202.

36. Zhang B, Yang G, Guo D, Wang J. Recent developments on NHC-driven dual catalytic approaches. Org Chem Front 2022;9:5016-40.

37. Zhang B, Wang J. Assembly of versatile fluorine-containing structures via N-heterocyclic carbene organocatalysis. Sci China Chem 2022;65:1691-703.

38. Gao J, Feng J, Du D. Generation of azolium dienolates as versatile nucleophilic synthons via N -heterocyclic carbene catalysis. Org Chem Front 2021;8:6138-66.

39. Bellotti P, Koy M, Hopkinson MN, Glorius F. Recent advances in the chemistry and applications of N-heterocyclic carbenes. Nat Rev Chem 2021;5:711-25.

40. Wadamoto M, Phillips EM, Reynolds TE, Scheidt KA. Enantioselective synthesis of alpha,alpha-disubstituted cyclopentenes by an N-heterocyclic carbene-catalyzed desymmetrization of 1,3-diketones. J Am Chem Soc 2007;129:10098-9.

41. Ema T, Akihara K, Obayashi R, Sakai T. Construction of contiguous tetrasubstituted carbon stereocenters by intramolecular crossed benzoin reactions catalyzed by N-Heterocyclic Carbene (NHC) organocatalyst. Adv Synth Catal 2012;354:3283-90.

42. Zhuo S, Zhu T, Zhou L, et al. Access to all-carbon spirocycles through a carbene and thiourea cocatalytic desymmetrization cascade reaction. Angew Chem Int Ed Engl 2019;58:1784-8.

43. Zhu T, Liu Y, Smetankova M, et al. Carbene-catalyzed desymmetrization and direct construction of arenes with all-carbon quaternary chiral center. Angew Chem 2019;131:15925-9.

44. Hu JM, Zhang JQ, Sun BB, et al. Chiral N-Heterocyclic-Carbene-Catalyzed cascade asymmetric desymmetrization of cyclopentenediones with enals: access to optically active 1,3-indandione derivatives. Org Lett 2019;21:8582-6.

45. Shee S, Mukherjee S, Gonnade RG, Biju AT. Enantioselective synthesis of tricyclic β-Lactones by NHC-Catalyzed desymmetrization of cyclic 1,3-Diketones. Org Lett 2020;22:5407-11.

46. Wang G, Zhang M, Guan Y, et al. Desymmetrization of cyclic 1,3-Diketones under N-Heterocyclic carbene organocatalysis: access to organofluorines with multiple stereogenic centers. Research 2021;2021:9867915.

47. Geng H, Chen X, Gui J, et al. Practical synthesis of C-1 deuterated aldehydes enabled by NHC catalysis. Nat Catal 2019;2:1071-7.

48. Zhang X, Chen Q, Song R, et al. Carbene-Catalyzed α,γ-Deuteration of enals under oxidative conditions. ACS Catal 2020;10:5475-82.

49. Sawama Y, Miki Y, Sajiki H. N-Heterocyclic carbene catalyzed deuteration of aldehydes in D2O. Synlett 2020;31:699-702.

50. Suresh P, Thamotharan S, Selva Ganesan S. NHC Organocatalysis in D2O for the highly diastereoselective synthesis of deuterated spiropyran analogues. ChemistrySelect 2021;6:2036-40.

51. Wang G, Fu Z, Huang W. Access to amide from aldimine via aerobic oxidative carbene catalysis and LiCl as cooperative lewis acid. Org Lett 2017;19:3362-5.

52. Zhang Y, Huang J, Guo Y, Li L, Fu Z, Huang W. Access to enantioenriched organosilanes from enals and β‐silyl enones: carbene organocatalysis. Angew Chem 2018;130:4684-8.

53. Wang G, Shi Q, Hu W, et al. Organocatalytic asymmetric N-sulfonyl amide C-N bond activation to access axially chiral biaryl amino acids. Nat Commun 2020;11:946.

54. Hu Z, Wei C, Shi Q, et al. Desymmetrization of N-Cbz glutarimides through N-heterocyclic carbene organocatalysis. Nat Commun 2022;13:4042.

55. Wang G, Zhang QC, Wei C, et al. Asymmetric Carbene-Catalyzed Oxidation of Functionalized Aldimines as 1,4-Dipoles. Angew Chem Int Ed Engl 2021;60:7913-9.

56. Wang G, Huang J, Zhang L, et al. N-heterocyclic carbene-catalyzed atroposelective synthesis of axially chiral 5-aryl 2-pyrones from enals. Sci China Chem 2022;65:1953-61.

57. Zhang C, Hooper JF, Lupton DW. N -Heterocyclic Carbene Catalysis via the α,β-Unsaturated Acyl Azolium. ACS Catal 2017;7:2583-96.

58. Ding A, Meazza M, Guo H, Yang JW, Rios R. New development in the enantioselective synthesis of spiro compounds. Chem Soc Rev 2018;47:5946-96.

59. Xu P, Yu J, Chen C, Cao Z, Zhou F, Zhou J. Catalytic enantioselective construction of spiro quaternary carbon stereocenters. ACS Catal 2019;9:1820-82.

60. Hong L, Wang R. Recent advances in asymmetric organocatalytic construction of 3,3′-spirocyclic oxindoles. Adv Synth Catal 2013;355:1023-52.

61. Cheng D, Ishihara Y, Tan B, Barbas CF. Organocatalytic asymmetric assembly reactions: synthesis of spirooxindoles via organocascade strategies. ACS Catal 2014;4:743-62.

Cite This Article

Short Communication
Open Access
Direct construction of d3-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization
Jingcheng Guo, ... Zhenqian Fu

How to Cite

Guo, J.; Zhang, Y.; Zhang, X.; Fu, Z. Direct construction of d3-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization. Chem. Synth. 2023, 3, 34. http://dx.doi.org/10.20517/cs.2023.04

Download Citation

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click on download.

Export Citation File:

Type of Import

Tips on Downloading Citation

This feature enables you to download the bibliographic information (also called citation data, header data, or metadata) for the articles on our site.

Citation Manager File Format

Use the radio buttons to choose how to format the bibliographic data you're harvesting. Several citation manager formats are available, including EndNote and BibTex.

Type of Import

If you have citation management software installed on your computer your Web browser should be able to import metadata directly into your reference database.

Direct Import: When the Direct Import option is selected (the default state), a dialogue box will give you the option to Save or Open the downloaded citation data. Choosing Open will either launch your citation manager or give you a choice of applications with which to use the metadata. The Save option saves the file locally for later use.

Indirect Import: When the Indirect Import option is selected, the metadata is displayed and may be copied and pasted as needed.

About This Article

Special Issue

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Data & Comments

Data

Views
506
Downloads
201
Citations
1
Comments
0
5

Comments

Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.

0
Download PDF
Share This Article
Scan the QR code for reading!
See Updates
Contents
Figures
Related
Chemical Synthesis
ISSN 2769-5247 (Online)

Portico

All published articles are preserved here permanently:

https://www.portico.org/publishers/oae/

Portico

All published articles are preserved here permanently:

https://www.portico.org/publishers/oae/