University of Groningen
Novel Methods towards Rare Sugars Based on Site-Selective Chemistry
Wan, Ieng Chim (Steven)
DOI:
10.33612/diss.150384050
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Publication date: 2021
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Wan, I. C. S. (2021). Novel Methods towards Rare Sugars Based on Site-Selective Chemistry. University of Groningen. https://doi.org/10.33612/diss.150384050
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Chapter 7:
Summary
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Rare monosaccharides are monosaccharides which are produced in minute amounts by many organisms, mainly bacteria. However, their low abundance does not imply triviality, as many of them are structural components of important natural products, such as anti-cancer agents and antibiotics.[1] The synthesis of such compounds is therefore an
important field in carbohydrate chemistry. Despite their minimal size (C6), their poly-hydroxylated structure with multiple stereocenters poses a non-trivial challenge for a bottom-up synthesis from achiral starting materials. A more tractable approach is to start from a molecule which has most of the existing functional group with the correct regiochemistry and stereochemistry, i.e. a common monosaccharide. With such an approach, minimal changes have to be made to the starting material for the synthesis of the target rare monosaccharide, thus shortening the synthesis. Nevertheless, desired modifications on common monosaccharides are often not straightforward due to the multiple hydroxyl groups which are similar in reactivity. In order to tackle this problem, carbohydrate chemists have devised multiple tools which are effective in differentiating different hydroxyl groups in monosaccharides. Among the existing strategies, silylation, esterification, and acetal/ketal formation are effective at differentiating different hydroxyl groups in common monosaccharides (i.e. they are site-selective). Due to their versatility, most of the rare monosaccharides synthesized chemically rely on such methodology. Some of these methodologies can even be extended to modify oligosaccharides and glycopeptides. However, all of these modifications are protective, i.e. they are seldom used for further functionalization and do not appear in the final product. Multiple protection and deprotection steps are often involved in the synthesis with only a few steps which are synthetically progressive towards the desired product. In recent years, progress has been made in direct site-selective modifications which lead to the desired product or versatile intermediates and allows further functionalization. Examples are oxidation,[2-3]
deoxygenation,[4] α-alkylation[5] and inversion.[6] Despite all the progress made, the
toolbox of site-selective modifications remains small. In the work described in this dissertation, different aspects of progressive site-selective modifications of monosaccharides were approached from different angles. New methodologies have been developed with photoredox catalysis, and the mechanism and the origin of selectivity observed in the transition metal catalyzed oxidation developed by our group is deciphered. While trying to apply our new methodology on the synthesis of N-acetyl talosaminuronic acid, a new shortcut towards N-acetylgulosamine was discovered by serendipity.
Chapter 2 describes the C3 selective α-alkylation of unprotected glucosides and
xylosides. By adapting the photoredox catalysis methodology originally developed by MacMillan and coworkers,[7] C3 selective hydrogen atom transfer (HAT) is induced in
glucosides and xylosides, forming an electron-rich carbon-centered radical at C3. Subsequent addition of this radical to various somophiles results in C3-branched allosides in ~50% isolated yield (Scheme 1).[8] Despite the remarkable selectivity, the reaction
suffers from moderate yields due to incomplete conversion and difficult isolation. Therefore, the reaction is studied extensively in Chapter 3. The reaction of α-methyl glucoside with phenyl vinyl sulfone is chosen as the benchmark reaction for the study. Optimization of the reaction in terms of both conversion and catalyst loading was attempted. During the study, the light sources were characterized, and side reactions of
phenyl vinyl sulfone were found to occur under the photochemical conditions used. To facilitate isolation, it was attempted to replace DMSO with other solvents, while trying to remove salts with extraction based on our knowledge on the Hofmeister series.
Scheme 1. Selective α-alkylation of α-methyl glucoside at C3. (Chapters 2 and 3) In Chapter 4, the challenge to prepare L-monosaccharides from common D -monosaccharides using photoredox catalysis is addressed (Scheme 2). By oxidizing and attaching a redox-active group on C6, decarboxylation can be induced, generating a carbon-centered radical at C5. By restricting the conformation of the radical intermediate, subsequent addition to a somophile occurs with high selectivity leading to the L -configured product in ~80% isolated yield. Using this methodology, L-guloside was
synthesized from D-mannoside in 6 steps and 21% yield, providing a new entry point of
L-monosaccharides from D-monosaccharides via inversion at C5.[9]
Scheme 2. Stereo-inversion at C5 using photoredox catalysis. (Chapter 4)
To capitalize on the success with the methodology on C5 inversion, we attempted to synthesize N-acetyl talosaminuronic acid from N-acetyl glucosamine in Chapter 5 by combining C3 inversion described previously in our group and C5 inversion (Scheme 3). However, during the synthesis of N-acetyl talosaminuronic acid, an unusual side product appeared during the reduction of 3-keto-N-acetyl glucosaminoside to N-acetyl allosaminoside. This turned out to be N-acetyl gulosaminoside. Subsequent optimization and mechanistic studies show that the epimerization does not happen during the reduction step, but rather with the product N-acetyl allosaminoside during workup with the acidic
170
resin Amberlite IR120 H. Although we were not able to pinpoint the mechanism, this reaction provides a novel starting point to the synthesis of acetyl gulosamine from N-acetyl glucosamine.
Scheme 3. Synthesis of N-acetyl gulosaminoside via reduction and epimerization at C4. (Chapter 5)
In Chapter 6, the in silico the origin of the C3 selectivity observed in the site-selective oxidation of methyl glucoside by Waymouth’s catalyst is investigated. Via activation strain analysis, it is shown that the selectivity is entirely substrate-controlled. Comparison of the energies of multiple 3-keto vs 2-keto systems unilaterally shows an intrinsic thermodynamic bias towards the 3-keto product, and subsequent energy decomposition analysis on the model systems demonstrates that the positive charge buildup during β-hydride elimination is disfavored when the site is in proximity to the ring oxygen, leaving C3 the “least disfavored” site for oxidation (Scheme 4). This aligns with the experimental results that the C3 selectivity entirely disappears when the ring oxygen is replaced by a methylene group.
References
[1] S. I. Elshahawi, K. A. Shaaban, M. K. Kharel, J. S. Thorson, Chem. Soc. Rev. 2015, 44, 7591–7697.
[2] M. Jäger, M. Hartmann, J. G. De Vries, A. J. Minnaard, Angew. Chemie - Int. Ed. 2013,
52, 7809–7812.
[3] K. Chung, R. M. Waymouth, ACS Catal. 2016, 6, 4653–4659.
[4] J. Zhang, N. N. H. M. Eisink, M. D. Witte, A. J. Minnaard, J. Org. Chem. 2019, 84, 516–525.
[5] V. Dimakos, H. Y. Su, G. E. Garrett, M. S. Taylor, J. Am. Chem. Soc. 2019, 141, 5149– 5153.
[6] Y. Wang, H. M. Carder, A. E. Wendlandt, Nature 2020, 578, 403–408.
[7] J. L. Jeffrey, J. A. Terrett, D. W. C. MacMillan, Science (80-. ). 2015, 349, 1532–1536. [8] I. C. Wan, M. D. Witte, A. J. Minnaard, Chem. Commun. 2017, 53, 4926–4929. [9] I. C. Wan, M. D. Witte, A. J. Minnaard, Org. Lett. 2019, 21, 7669–7673.
