Total Synthesis of Trisaccharide Repeating Unit of <i>Staphylococcus aureus</i> Type 8 (CP8) Capsular Polysaccharide

Rai, Diksha; Kulkarni, Suvarn S.

doi:10.1021/acs.orglett.3c00290

Cited by 10 publications

(7 citation statements)

References 36 publications

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“…Access to these molecules will depend on innovations to de novo synthesis and feedstock carbohydrate modification. , Previously, our group and others have focused on methods to synthesize 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose, colloquially known as AAT, 60 . Each synthesis is arduous and generally ranges from 10 to 15 steps. ,− If the technology were available to deoxygenate carbon atoms site specifically and convert alcohols directly to amines (with either retention or inversion of stereochemistry), synthesis of bacterial monosaccharides would be significantly enhanced. …”

Section: Problem Selectionmentioning

confidence: 99%

A Hitchhiker’s Guide to Problem Selection in Carbohydrate Synthesis

Streety,

Obike,

Townsend

2023

ACS Cent. Sci.

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Oligosaccharides are ubiquitous in molecular biology and are used for functions ranging from governing protein folding to intercellular communication. Perhaps paradoxically, the exact role of the glycan in most of these settings is not well understood. One reason for this contradiction concerns the fact that carbohydrates often appear in heterogeneous form in nature. These mixtures complicate the isolation of pure material and characterization of structure−activity relationships. As a result, a major bottleneck in glycoscience research is the synthesis and modification of pure materials. While synthetic and chemoenzymatic methods have enabled access to homogeneous tool compounds, a central problem, particularly for newer synthetic chemists, is the matter of problem selection. This outlook aims to provide an entry level overview of fundamental principles in carbohydrate chemistry with an eye toward enabling solutions to frontier challenges.

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Section: Problem Selectionmentioning

confidence: 99%

A Hitchhiker’s Guide to Problem Selection in Carbohydrate Synthesis

Streety,

Obike,

Townsend

2023

ACS Cent. Sci.

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“…The downfield shift of the characteristic doublet of doublet for H-3 at 4.99 ppm (J = 9.8, 3.1 Hz, H-3) clearly confirmed the presence of an acetyl group at the C3 position in compound 14. As shown in Scheme 2b, the known L-rhamnosyl diol 15 25 on benzylation followed by denaphthylmethylation using DDQ afforded 3-hydroxy-L-rhamnose derivative 16 in 82% yield over In order to address the challenging stereoselective glycosylation in super armed dideoxy thioglycoside donor 3, we resorted to Mong's DMF modulated preactivation glycosylation 13 method after testing standard glycosylation methods (see the Supporting Information, Table S1). Here, thioglycosyl donor 5 was activated to form the corresponding DMF imidate using NIS, TMSOTf, and DMF (Table 1, entries 1−3) at −78 °C and slowly warming to −50 °C which upon further addition of 1.2 equiv of acceptor gave a hemiacetal of the donor with only a trace amount of product (as judged by HRMS).…”

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confidence: 99%

Total Synthesis of a Conjugation-Ready Tetrasaccharide Repeating Unit of Vibrio cholerae O:3 O-antigen Polysaccharide

Maji,

Ghotekar,

Kulkarni

2024

Org. Lett.

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Herein, we report the first total synthesis of the tetrasaccharide repeating unit of Vibrio cholerae O:3 O-antigen polysaccharide. The highly complex tetrasaccharide contains rare amino sugars such as D-bacillosamine and L-fucosamine, highly labile sugar ascarylose, and higher carbon sugar D-D-heptose. Stereoselective glycosylation of the notoriously reactive ascarylose with D-D-heptose, poor nucleophilicity of the axial C4-OH of Lfucosamine, and amide coupling are the key challenges encountered in the total synthesis, which was completed via a longest linear sequence of 23 steps in 4.2% overall yield.Vibrio cholerae is a Gram-negative, facultative anaerobic, and comma-shaped bacteria, commonly found in contaminated water and food. According to the WHO fact sheet, Vibrio cholerae is a highly contagious pathogen, causing over 1 million cases of diarrhea and a significant number of deaths globally every year. 1 The world has faced seven massive cholerae pandemics, epidemics, endemics, and seasonal or sporadic outbreaks. V. cholerae can survive in adverse aquatic environments for prolonged periods, which makes the bacteria highly virulent. 2 This high-risk bacterium can cause watery diarrhea associated with dehydration, vomiting, unconsciousness, and death within a few hours if left untreated. Furthermore, epidemiological study proves that V. cholerae shows antimicrobial resistance toward first-and second-line antibiotics. 3 The prophylaxis strategies are therefore required to curb the disease. There are a few oral cholera vaccines (OCVs) approved by WHO. However, degradation of the antigen exposed to acidic pH in the stomach and short-lived immune protection leaves room for further development for a multicomponent glycoconjugate vaccine against all O-antigen serogroups of V. cholerae. 4 There are more than 200 serogroups based on O-antigen of the lipopolysaccharide present on the bacterial cell surface. 2 Recently, strain O:3 was detected in the archived clinical isolates obtained from cholera outbreaks that took place in southern Ghana during 2012− 2015. 3 Surface exposed carbohydrates are antigenic materials and are key components of a glycoconjugate vaccine. 5 Also, they are known to be safe and create a long-lasting T-cell-dependent memory, upon protein conjugation. 6 The bacterial cell surface carries glycoconjugates and oligosaccharides containing rare deoxy amino sugars that are absent in human cells. 7 This critical difference can be exploited to develop carbohydrate-

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“…For the coupling with a more reactive primary alcohol 10, we opted for Demchenko's picoloylmediated HAD glycosylation using donor 9 to install the 1,2-cis linkage with a highly reactive primary alcohol 10, which was thought to be more challenging. 16 Our synthesis commenced with the procurement of orthogonally protected rare sugar L-quinovosamine building blocks starting from known L-rhamnose diols 11 17 and 12 18 (Scheme 2). Regioselective OTBS protection 19 of the equatorial C4-OH in compound 11 gave the corresponding C4 silylated compound in 85% yield.…”

mentioning

confidence: 99%

“…Our synthesis commenced with the procurement of orthogonally protected rare sugar l -quinovosamine building blocks starting from known l -rhamnose diols 11 and 12 (Scheme ). Regioselective OTBS protection of the equatorial C4-OH in compound 11 gave the corresponding C4 silylated compound in 85% yield.…”

mentioning

confidence: 99%