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Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 15363

Special Issue Editor

Dr. Indrajeet Sharma

E-Mail Website
Guest Editor
Chemistry and Biochemistry Department, University of Oklahoma, Norman, OK, USA
Interests: carbohydrate chemistry; drug discovery; metal carbenes; nitrenes; natural products

Special Issue Information

Dear Colleagues,

We are pleased to announce a Special Issue in honor of Professor David Crich, celebrating his remarkable contributions to Carbohydrate Chemistry on his 65th birthday. Over the years, Professor Crich has made outstanding strides in this intricate and pivotal area of science, specifically on the novel methods for stereoselective glycosylation, leaving an indelible mark on the community. His innovative approaches and mechanistic studies have opened new frontiers in carbohydrate chemistry, addressing complex challenges and laying the foundation for groundbreaking research. This Special Issue will serve as a tribute to Professor Crich’s lifelong dedication to carbohydrate chemistry and will feature a collection of articles, reviews, and research papers.

We invite researchers and scholars from around the world to contribute to this Special Issue, sharing their own insights and discoveries inspired by Professor Crich's work. This collective effort will showcase carbohydrate chemistry’s ongoing relevance and significance, as well as its potential to address critical scientific questions and challenges. We encourage you to participate in this tribute to Professor Crich's extraordinary career and to celebrate the profound influence he has had on the field of carbohydrate chemistry. Please submit your manuscripts, reviews, or other contributions by May 31 2024 to be considered for inclusion in this Special Issue.

We look forward to celebrating Professor Crich’s 65th birthday and his legacy in carbohydrate chemistry through this Special Issue.

Dr. Indrajeet Sharma
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • carbohydrate chemistry
  • stereoselective glycosylation
  • anomeric effect
  • sialic acids
  • stereoselective furanosylation
  • glycans
  • oligosaccharides
  • glycoconjugates

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Published Papers (12 papers)

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Research

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18 pages, 2579 KiB  
Article
Anomerization of N-Acetylglucosamine Glycosides Promoted by Dibromomethane and Dimethylformamide
by Natalie B. Condino, Doriane Rousseau, Esperance Mutoni, Jeffrey Davidson, Lara K. Watanabe and France-Isabelle Auzanneau
Molecules 2025, 30(7), 1483; https://doi.org/10.3390/molecules30071483 - 27 Mar 2025
Viewed by 255
Abstract
In previous quests to synthesize fragments of tumor-associated carbohydrate antigens (TACAs), we determined that bromoalkyl β glycosides of N-acetylglucosamine were labile and incompatible with some of the synthetic conditions required for the preparation of oligosaccharides. While N-acetylglucosamine chloroalkyl β glycosides are [...] Read more.
In previous quests to synthesize fragments of tumor-associated carbohydrate antigens (TACAs), we determined that bromoalkyl β glycosides of N-acetylglucosamine were labile and incompatible with some of the synthetic conditions required for the preparation of oligosaccharides. While N-acetylglucosamine chloroalkyl β glycosides are common intermediates for oligosaccharide synthesis, they exhibit poor yields upon subsequent reactions used to introduce the oxyamine required for further conjugation. Thus, we looked to synthesize these TACAs using chloroalkyl β glycosides and substitute the chlorine for bromine at a later synthetic stage. Upon substitution of the bromine for chlorine using sodium bromide in a dibromomethane (DBM) dimethylformamide (DMF) mixture, we observed the unexpected anomerization of the N-acetylglucosamine β glycosides, yielding up to 90% of the α glycosides. We describe our studies of this unexpected anomerization and report on how the anomeric ratios can be controlled experimentally. Interestingly, we also report the anomerization of alkyl β glycosides of N-acetylglucosamine in a mixture of DBM and DMF without sodium bromide. Further studies are being conducted to determine the mechanism of this anomerization and the scope of this reaction. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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18 pages, 4028 KiB  
Article
Exploration of the Fusidic Acid Structure Activity Space for Antibiotic Activity
by Yoon-Suk Kang, Simone C. Silva, Kenneth Smith, Krissty Sumida, Yuhan Wang, Lucius Chiaraviglio, Ramachandra Reddy Donthiri, Alhanouf Z. Aljahdali, James E. Kirby and George A. O’Doherty
Molecules 2025, 30(3), 465; https://doi.org/10.3390/molecules30030465 - 21 Jan 2025
Viewed by 708
Abstract
Fusidic acid is a translation inhibitor with activity against major Gram-positive bacterial pathogens such as S. aureus. However, its activity against Gram-negatives is poor based on an inability to access its cytoplasmic target in these organisms. Opportunities for functionalization of the fusidic [...] Read more.
Fusidic acid is a translation inhibitor with activity against major Gram-positive bacterial pathogens such as S. aureus. However, its activity against Gram-negatives is poor based on an inability to access its cytoplasmic target in these organisms. Opportunities for functionalization of the fusidic acid scaffold to enhance activity against Gram-negative pathogens have not been explored. Using an activity-guided synthetic strategy, the tolerance of the tetracyclic natural product to derivatization at the A- and C-rings and its carboxylic acid side chain was explored with the goal of enhancing its activity spectrum and pharmacological properties. All side-chain carboxylic acid esters were inactive. Oxidation of the C-ring alcohol and oxime were not tolerated either. A number of esters of the A-ring alcohol retained modest activity against Gram-positive bacteria and were informative for future activity-guided studies. For the A-ring esters, differences in antibacterial activity relative to inhibitory activity in a ribosome in vitro translation assay suggested the possibility of a pro-druglike effect for the fusidic acid pyrazine-2-carboxylate. This study furthers the understanding of the activity of the fusidic acid scaffold against Gram-positive bacteria. These results suggest promise for future modification of the A-ring alcohol of fusidic acid in the advancement of its antibiotic properties. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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12 pages, 861 KiB  
Article
Stereoelectronic Effect of Protecting Groups on the Stability of Galactosyl Donor Intermediates
by Ryan W. Kwok, Ryan Rutkoski, Pavel Nagorny and Mateusz Marianski
Molecules 2025, 30(2), 218; https://doi.org/10.3390/molecules30020218 - 7 Jan 2025
Viewed by 912
Abstract
Using methods of DFT, we investigated the effect of electron withdrawing and electron donating groups on the relative stability of tentative glycosyl donor reaction intermediates. The calculation shows that by changing the stereoelectronic properties of the protecting group, we can influence the stability [...] Read more.
Using methods of DFT, we investigated the effect of electron withdrawing and electron donating groups on the relative stability of tentative glycosyl donor reaction intermediates. The calculation shows that by changing the stereoelectronic properties of the protecting group, we can influence the stability of the dioxolenium type of intermediates by up to 10 kcal mol−1, and that by increasing nucleophillicity of the 4-O-Bz group, the dioxolenium intermediate becomes more stable than a triflate–donor pair. We exploited this mechanism to design galactosyl donors with custom protecting groups on O2 and O4, and investigated the outcome of the reaction with cyclohexanol. The reaction showed no change in the product distribution, which suggests that the neighboring group participation takes precedence over remote group participation due to kinetic barriers. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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25 pages, 3104 KiB  
Article
Synthesis of S-Glycoside Building Blocks as Mimetics of the Repeating d-GlcN-α-1,4-d-GlcA Heparan Sulfate Disaccharide
by Conor O’Shea and Gavin J. Miller
Molecules 2024, 29(23), 5809; https://doi.org/10.3390/molecules29235809 - 9 Dec 2024
Cited by 1 | Viewed by 968
Abstract
Heparan sulfate (HS), a sulfated linear carbohydrate that decorates the cell surface and extracellular matrix, is a key regulator of biological processes. Owing to the inherent structural complexity of HS, structure-to-function studies with its ligands are required, and materials to improve the understanding [...] Read more.
Heparan sulfate (HS), a sulfated linear carbohydrate that decorates the cell surface and extracellular matrix, is a key regulator of biological processes. Owing to the inherent structural complexity of HS, structure-to-function studies with its ligands are required, and materials to improve the understanding of such interactions are therefore of high importance. Herein, the synthesis of novel S-linked GlcN-α(1→4)-GlcA disaccharide building blocks is detailed. Initial attempts at constructing the desired disaccharide using d-GlcN donors and d-Glc/GlcA acceptors via an S-glycosylation failed. Reversing the reactivity polarity of the monosaccharide building blocks enabled successful SN2 coupling using α-d-GlcN thiohemiacetals and d-galactosyl triflates. Subsequent C6-oxidation furnished the desired S-linked GlcN-α(1→4)-GlcA disaccharide building blocks on a gram scale. Such disaccharides offer potential for incorporation into wider synthetic HS sequences to provide glycomimetic tools. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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20 pages, 2202 KiB  
Article
Catalytic Thioglycoside Activation with Diazo-Derived Copper Carbenes
by Surya Pratap Singh, Umesh Chaudhary and Indrajeet Sharma
Molecules 2024, 29(22), 5367; https://doi.org/10.3390/molecules29225367 - 14 Nov 2024
Cited by 1 | Viewed by 2095
Abstract
Traditional glycosylation methods using thioglycosides often require harsh conditions or expensive metal catalysts. This study presents a more sustainable alternative by employing copper, an earth-abundant catalyst. We developed diazo-based thioglycoside donors that, through copper catalysis, undergo intramolecular activation to form glycosyl sulfonium ions, [...] Read more.
Traditional glycosylation methods using thioglycosides often require harsh conditions or expensive metal catalysts. This study presents a more sustainable alternative by employing copper, an earth-abundant catalyst. We developed diazo-based thioglycoside donors that, through copper catalysis, undergo intramolecular activation to form glycosyl sulfonium ions, leading to the generation of oxocarbenium ions. This versatile approach efficiently accommodates a variety of O-nucleophiles, including primary, secondary, and tertiary, as well as complex bioactive molecules. It is compatible with various glycosyl donors and protecting groups, including superarmed, armed, and disarmed systems. Notably, the methodology operates orthogonally to traditional thioglycoside and alkyne donors and has been successfully applied to the orthogonal iterative synthesis of trisaccharides. Mechanistic insights were gained by studying the electronic effects of electron-donating (OMe) and electron-withdrawing (NO2) groups on the donors, offering a valuable understanding of the intramolecular reaction pathway. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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9 pages, 430 KiB  
Article
Chemical Synthesis of 6-Azido-6-Deoxy Derivatives of Phosphatidylinositol Containing Different Fatty Acid Chains
by Mosidur Rahaman Molla, Palak Gupta, Rajendra Rohokale and Zhongwu Guo
Molecules 2024, 29(21), 4981; https://doi.org/10.3390/molecules29214981 - 22 Oct 2024
Viewed by 1558
Abstract
This paper describes the synthesis of two 6-azido-6-deoxy derivatives of phosphatidylinositol (PI), which contained different fatty acid chains. These syntheses, starting from methyl α-d-glucopyranoside, employed multiple regioselective transformations with Ferrier rearrangement as one of the key steps. The PI derivatives contained different fatty [...] Read more.
This paper describes the synthesis of two 6-azido-6-deoxy derivatives of phosphatidylinositol (PI), which contained different fatty acid chains. These syntheses, starting from methyl α-d-glucopyranoside, employed multiple regioselective transformations with Ferrier rearrangement as one of the key steps. The PI derivatives contained different fatty acid chains in the lipids and an azido group in the inositol residue to facilitate their further functionalization under bioorthogonal conditions. Therefore, they should be useful probes for the investigation of PI and related biology, such as PI phosphorylation, PI interaction with other molecules in cells, and the functions of lipid structures in these processes. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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13 pages, 1971 KiB  
Article
Mechanism-Based Allylic Carbasugar Chlorides That Form Covalent Intermediates with α- and β-Galactosidases
by Oluwafemi Akintola, Sandeep Bhosale and Andrew J. Bennet
Molecules 2024, 29(20), 4870; https://doi.org/10.3390/molecules29204870 - 14 Oct 2024
Viewed by 1072
Abstract
Glycoside hydrolases have been implicated in a wide range of human conditions including lysosomal storage diseases. Consequently, many researchers have directed their efforts towards identifying new classes of glycoside hydrolase inhibitors, both synthetic and from natural sources. A large percentage of such inhibitors [...] Read more.
Glycoside hydrolases have been implicated in a wide range of human conditions including lysosomal storage diseases. Consequently, many researchers have directed their efforts towards identifying new classes of glycoside hydrolase inhibitors, both synthetic and from natural sources. A large percentage of such inhibitors are reversible competitive inhibitors that bind in the active site often due to them possessing structural features, often a protonatable basic nitrogen atom, that mimic the enzymatic transition state. We report that mechanism-based small molecule galacto-like configured cyclohexenyl carbasugars form reversible covalent complexes with both α-galactosidase and β-galactosidase. In addition, we show that the β-galactosidase from Aspergillus oryzae reacts with three different carbasugar inhibitors, with three different second-order rate constants (kinact/Ki), to give the same enzyme–carbasugar covalent intermediate. The surprising observation that the α-galacto-configured inhibitor covalently labels the A. oryzae β-galactosidase highlights the catalytic versatility of glycoside hydrolases. We expect that cyclohexenyl covalent inhibitors will become an important class of compounds in the chemical biologist’s tool box. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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10 pages, 4000 KiB  
Article
Ferric Chloride Promoted Glycosidation of Alkyl Thioglycosides
by Lacie M. Ridgway, Anupama Das, Melanie L. Shadrick and Alexei V. Demchenko
Molecules 2024, 29(20), 4845; https://doi.org/10.3390/molecules29204845 - 13 Oct 2024
Viewed by 1155
Abstract
Reported herein is a new reaction for glycosylation with thioglycosides in the presence of iron(III) chloride. Previously, FeCl3 was used for the activation of thioglycosides as a Lewis acid co-promoter paired with NIS. In the reported process, although 5.0 equiv of FeCl [...] Read more.
Reported herein is a new reaction for glycosylation with thioglycosides in the presence of iron(III) chloride. Previously, FeCl3 was used for the activation of thioglycosides as a Lewis acid co-promoter paired with NIS. In the reported process, although 5.0 equiv of FeCl3 are needed to activate thioglycosides most efficiently, no additives were used, and the reactions with reactive glycosyl donors smoothly proceeded to completion in 1 h at 0 °C. This work showcases a new direction in developing glycosylation methods using greener and earth-abundant activators. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
27 pages, 3655 KiB  
Article
Towards New Delivery Agents for Boron Neutron Capture Therapy: Synthesis and In Vitro Evaluation of a Set of Fluorinated Carbohydrate Derivatives
by Jelena Matović, Juulia Järvinen, Iris K. Sokka, Surachet Imlimthan, Olli Aitio, Mirkka Sarparanta, Jarkko Rautio and Filip S. Ekholm
Molecules 2024, 29(17), 4263; https://doi.org/10.3390/molecules29174263 - 9 Sep 2024
Viewed by 1701
Abstract
Boron Neutron Capture Therapy (BNCT) is a cancer treatment which combines tumor-selective boron delivery agents with thermal neutrons in order to selectively eradicate cancer cells. In this work, we focus on the early-stage development of carbohydrate delivery agents for BNCT. In more detail, [...] Read more.
Boron Neutron Capture Therapy (BNCT) is a cancer treatment which combines tumor-selective boron delivery agents with thermal neutrons in order to selectively eradicate cancer cells. In this work, we focus on the early-stage development of carbohydrate delivery agents for BNCT. In more detail, we expand upon our previous GLUT-targeting approach by synthesizing and evaluating the potential embedded in a representative set of fluorinated carbohydrates bearing a boron cluster. Our findings indicate that these species may have advantages over the boron delivery agents in current clinical use, e.g., significantly improved boron delivery capacity at the cellular level. Simultaneously, the carbohydrate delivery agents were found to bind strongly to plasma proteins, which may be a concern requiring further action before progression to in vivo studies. Altogether, this work brings new insights into factors which need to be accounted for if attempting to develop theranostic agents for BNCT based on carbohydrates in the future. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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12 pages, 2083 KiB  
Article
Incorporation of an Isohexide Subunit into the Endochin-like Quinolone Scaffold
by Julia Senkina and Spencer Knapp
Molecules 2024, 29(15), 3615; https://doi.org/10.3390/molecules29153615 - 31 Jul 2024
Cited by 1 | Viewed by 1033
Abstract
In order to improve the drug-likeness qualities, the antimalarial endochin-like quinolone (ELQ) scaffold has been modified by replacing the 4-(trifluoromethoxy)phenyl portion with an isoidide unit that is further adjustable by varying the distal O-substituents. As expected, the water solubilities of the new analogs [...] Read more.
In order to improve the drug-likeness qualities, the antimalarial endochin-like quinolone (ELQ) scaffold has been modified by replacing the 4-(trifluoromethoxy)phenyl portion with an isoidide unit that is further adjustable by varying the distal O-substituents. As expected, the water solubilities of the new analogs are greatly improved, and the melting points are lower. However, the antimalarial potency of the new analogs is reduced to EC50 > 1 millimolar, a result ascribable to the hydrophilic nature of the new substitution. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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9 pages, 1465 KiB  
Communication
Synthesis of a Borrelia burgdorferi-Derived Muropeptide Standard Fragment Library
by Rachel Putnik, Junhui Zhou, Irnov Irnov, Elise Garner, Min Liu, Klare L. Bersch, Christine Jacobs-Wagner and Catherine Leimkuhler Grimes
Molecules 2024, 29(14), 3297; https://doi.org/10.3390/molecules29143297 - 12 Jul 2024
Cited by 2 | Viewed by 1557
Abstract
The interplay between the human innate immune system and bacterial cell wall components is pivotal in understanding diseases such as Crohn’s disease and Lyme arthritis. Lyme disease, caused by Borrelia burgdorferi, is the most prevalent tick-borne illness in the United States, with [...] Read more.
The interplay between the human innate immune system and bacterial cell wall components is pivotal in understanding diseases such as Crohn’s disease and Lyme arthritis. Lyme disease, caused by Borrelia burgdorferi, is the most prevalent tick-borne illness in the United States, with a substantial number of cases reported annually. While antibiotic treatments are generally effective, approximately 10% of Lyme disease cases develop persistent arthritis, suggesting a dysregulated host immune response. We have previously identified a link between the immunogenic B. burgdorferi peptidoglycan (PG) and Lyme arthritis and showed that this pathogen sheds significant amounts of PG fragments during growth. Here, we synthesize these PG fragments, including ornithine-containing monosaccharides and disaccharides, to mimic the unique composition of Borrelia cell walls, using reproducible and rigorous synthetic methods. This synthetic approach allows for the modular preparation of PG derivatives, providing a diverse library of well-defined fragments. These fragments will serve as valuable tools for investigating the role of PG-mediated innate immune response in Lyme disease and aid in the development of improved diagnostic methods and treatment strategies. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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Review

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22 pages, 4612 KiB  
Review
Stereoselective Approaches to β-Linked 2-Deoxy Sugars
by Clay S. Bennett
Molecules 2025, 30(7), 1578; https://doi.org/10.3390/molecules30071578 - 1 Apr 2025
Viewed by 296
Abstract
This review presents a survey of recent developments in the synthesis of β-linked 2-deoxy sugars. Approaches ranging from catalysis to de novo synthesis are described, with a focus on methods developed in the last 10 years. Where relevant, the application of these technologies [...] Read more.
This review presents a survey of recent developments in the synthesis of β-linked 2-deoxy sugars. Approaches ranging from catalysis to de novo synthesis are described, with a focus on methods developed in the last 10 years. Where relevant, the application of these technologies to synthesis and mechanistic information is discussed. Finally, it concludes with an examination of the scope and limitations of these technologies, as well as examinations about where the field should head next. Full article
(This article belongs to the Special Issue Special Issue in Honor of Prof. David Crich’s 65th Birthday for His Outstanding Contributions to Carbohydrate Chemistry)
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