University of Groningen
Regioselective modification of carbohydrates for their application as building blocks in
synthesis
Zhang, Ji
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Publication date: 2019
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Zhang, J. (2019). Regioselective modification of carbohydrates for their application as building blocks in synthesis. Rijksuniversiteit Groningen.
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Chapter 7
Summary, conclusion and outlook
In this chapter, a summary of all the chapters is given, future directions and some important ideas are provided on the basis of our work.
7.1 Summary and conclusion
In chapter 1, I presented several literature examples to discuss the progress in site-selective modification of carbohydrates using unprotected or partly protected starting materials. The focus in this chapter is on reagents or catalysts that recognize the anomeric hydroxyl group and secondary hydroxyl groups over the other hydroxyls groups in carbohydrates and that show a good selectivity and activity. Novel and more efficient ways have been developed to modify unprotected carbohydrates, but it is clear that, compared to the multitude of protecting group strategies available, the field is still in its infancy. In addition, even elegant approaches are not necessarily very useful. Selective protection (or arylation for example) of saccharides does not bring the synthesis of rare sugars much closer.
In chapter 2, I described the application of mono-Boc-protected hydrazine in Ugi tetrazole synthesis. Various aldehydes, ketones and isocyanides were studied in this reaction. The reaction enables the preparation of a library of highly substituted 5-(hydrazinomethyl)-1-methyl-1H-tetrazoles. We found that a catalytic amount of ZnCl2 can efficiently improve the yield in this reaction.
Subsequent deprotection of the Ugi tetrazole intermediates under acidic conditions afforded the final products in useful yields.
Scheme 1. Ugi tetrazole route to highly substituted 5-(hydrazinomethyl)-
1-methyl-1H-tetrazoles
In chapter 3, I described a novel approach to prepare anomeric sugar isocyanides. These sugar isocyanides were successfully used in isocyanide based multicomponent reactions, including the classical Ugi reactions and variations thereof (Scheme 2).
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Scheme 2. Novel approach to anomeric sugar isocyanides and their application in
multicomponent reaction
In chapter 4, we successfully employed our in-house developed catalytic regioselective oxidation of carbohydrates for the preparation of allosamine, N-acetyl allosamine, lividosamine and related compounds from N-N-acetyl glucosamine. We also showed the first successful example of the application of the Passerini reaction on 3-keto GlcNAc. This proof-of-concept reaction indicates that the MCRs are feasible on unprotected 3-keto saccharides and it thus provides a new way to modify glycosides at C3. It is possible to modify the C3 position in glucosamines in the presence of the other hydroxyl groups.
In chapter 5, I modified the 3-OH group of streptozotocin (STZ) to obtain allo-streptozotocin (allo-STZ), 3-keto-streptozotocin (keto-STZ) and 3-deoxy-streptozotocin (deoxy-STZ) with the aim to reduce the cytotoxicity while maintaining the bactericidal activity. Compared with STZ, both the antibacterial activity and the toxicity to -cells of all these three STZ analogues drops. The antibacterial activity of keto-STZ is stronger than allo-STZ and deoxy-STZ.
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In chapter 6, I describe a novel method for the introduction of a chloride at the C3 position in pyranosides. The method is based on our site-selective oxidation followed by reductive chlorination of the corresponding trityl hydrazone. The method was successfully applied to monosaccharides and disaccharides. First, the substrates were selectively oxidized to the corresponding 3-ketoses and then all 3-ketoses were converted to corresponding trityl hydrazones. The reductive chlorination process involves the reaction of the 3-trityl hydrazone with tBuOCl to form a diazene which readily decomposes to the
-chlorocarbinyl radical. Reaction of this radical by EtSH or tBuSH as the H-atom donor gave the corresponding chlorides.
7.2 Outlook
In chapter 4, we have applied the Passerini reaction to 3-keto-GlcNAc. Treatment of 3-keto-GlcNAc with benzyl isocyanide and benzoic acid in THF/DCM gave 2a and 2b (Scheme 3a). Hydrolysis of the products provided 3 (scheme 3a). This successful example paves the road for other multicomponent reactions on 3-keto-glycosides. If we swap the benzyl isocyanide to a sugar isocyanide 4 (as described in Chapter 3), perhaps it will give a disaccharide analogue connected via an amide group as shown in scheme 1b. The feasibility of the Passerini tetrazole synthesis1 (scheme 3c),the “normal” Ugi reaction2
(scheme 3d) and the Ugi tetrazole3 synthesis (scheme 3e) may be assessed using
3-keto-GlcNAc as a substrate. Ultimately, many different modifications can be performed with our 3-keto sugars, which should result in a library of carbohydrate analogs. The Van Leusen reaction would be another, very interesting, reaction to study.4 This reaction, using the anion of tosyl methyl
isocyanide (TosMic) leads to the conversion of a ketone into its homologous nitrile. Although not without pitfalls (the anion is quite basic and also sterically congested), the reaction would provide interesting carbohydrate analogues as shown in scheme 3f.
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Scheme 3. The application of multicomponent reactions to 3-keto GlcNAc
In chapter 6, we attempted to separate the epimeric mixture of 3-chloro maltose and 3-chloro cellulose. Since the Rf values of the equatorial and the axial chloride are very similar, only the pure axial chloride could be isolated. The 3-equatorial chloride still contained the 3-axial chloride. To improve the separation, we plan to introduce a more bulky and lipophilic group 4-tert-butylbenzyl group to replace the benzyl group, as shown in scheme 2a. Because this group will make the 3-chlorides less polar, it may also increase the difference in Rf values of the equatorial and the axial chloride which will facilitate the separation. In other words, 4-tert-butylbenzyl maltose and 4-tert-butylbenzyl cellobiose will be prepared. The synthesis route for the required 4-tert-butylbenzyl maltoside and 4-tert-butylbenzyl cellobioside will be similar to that of benzyl maltoside and benzyl cellobioside. The only difference will be the third step as benzyl bromide will be replaced by 4-tert-butylbenzyl bromide. De-acetylation of 5 and 7 in the presence of a catalytic amount of NaOMe in methanol will afford 6 and 8. These analogs will be subsequently converted into the 3-chloro maltosides and cellobiosides via the procedure we have described in chapter 6 (Scheme 2b).
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Scheme 4. Synthesis of 4-tert benzyl--D-cellobioside and 4-tert benzyl--D-maltoside
Upon separation of the equatorial and the axial chloride, axial chloride 22 may be used to prepare oligosaccharide derivatives via nucleophilic substitution with a sugar thiol (scheme 3).
Tumor formation is accompanied by aberrant glycosylation of glycoproteins and glycolipids. This is due to overexpression of glycosyltransferase N-acetyl glucosaminyl transferase V (GlcNAc-TV).5
GlcNAc-TV is responsible for the introduction of acetylglucosamine moiety to the N-linked oligosaccharides of glycoproteins, leading to the formation of the precursor for polylactosamine chains. These polysaccharides strengthen adhesion turnover, cell migration, and tumor metastasis.5 Thioglycosidic sugars
can inhibit GlcNAc-TV.5 Maybe it will be possible to inhibit GlcNAc-TV as an aid
in treating malignancies. The bioactivity of thioglycosidic sugars deserves more attention anyway. I propose that 1-thio-β-maltose 9 reacts with 4-tert-butylbenzyl
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3-chloro-3-deoxy--D-maltoside 10 to obtain 11. Chlorides can also be substituted by other groups such as azide, followed by click chemistry with terminal alkynes to form triazoles (scheme 3b).6
Scheme 5. The synthesis of thiol sugar and N-linked triazole.
In conclusion, we have shown some interesting modification at C3 of glycosides in this thesis, a lot of exploration can continue on the basis of selective oxidation at C3 of glycosides, especially the potential bioactivity of the glycosides after modification at C3 are deservesmore research.
3.5 References
(1) Chandgude, A. L.; Dömling, A. An efficient Passerini tetrazole reaction (PT-3CR). Green Chem. 2016, 18, 3718-3721.
(2) Ugi, I. The α-Addition of Immonium Ions and Anions to Isonitriles Accompanied by Secondary Reactions. Angew. Chem. Int. Ed. 1962, 1, 8-21.
(3) Zhao, T.; Boltjes, A.; Herdtweck, E.; Dömling, A. Tritylamine as an Ammonia Surrogate in the Ugi Tetrazole Synthesis. Org. Lett. 2013, 15, 639-641.
(4) Oldenziel, O. H.; Van Leusen, D.; Van Leusen, A. M., Chemistry of sulfonylmethyl isocyanides. 13. A general one-step synthesis of nitriles
159 from ketones using tosylmethyl isocyanide. Introduction of a one-carbon unit. J. Org. Chem. 1977, 42, 3114-3118.
(5) Zhong, W.; Kuntz, D. A.; Ember, B.; Singh, H.; Moremen, K. W.; Rose, D. R.; Boons, G.-J. Probing the Substrate Specificity of Golgi α-Mannosidase II by Use of Synthetic Oligosaccharides and a Catalytic Nucleophile Mutant. J. Am. Chem. Soc. 2008, 130, 8975-8983.
(6) Lim, D.; Brimble, M. A.; Kowalczyk, R.; Watson, A. J. A.; Fairbanks, A. J. Protecting-Group-Free One-Pot Synthesis of Glycoconjugates Directly from Reducing Sugars. Angew. Chem. Int. Ed. 2014, 53, 11907-11911.
