The synthesis of both enantiomers of lactobacillic acid and mycolic acid analogues

Coxon, Geoffrey D.; Knobl, Stefan; Roberts, Evan; Baird, Mark S.; Dulayymi, Juma’a R. Al; Besra, Gurdyal S.; Brennan, Patrick J.; Minnikin, David E.

doi:10.1016/s0040-4039(99)01378-7

Cited by 20 publications

(8 citation statements)

References 17 publications

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“…Here, we addressed this problem by studying the role in airway immune responses of the MA oxygenation class, defined by the distal meromycolic moiety, and the proximal cyclopropane stereochemical configuration. This was made possible because of recent advances in the chemical synthesis of single M. tuberculosis MAs 47–58.…”

Section: Discussionmentioning

confidence: 99%

“…The natural MA reference used was extracted from M. tuberculosis H37Rv ( M.tb .‐MA) and purchased from Sigma (St. Louis, MO, USA). The synthesis of the chemically defined synthetic MA isomers has been described before 47–58. The α‐methyl‐ trans methoxy‐MA ( trans ‐mMA) was prepared by a variation of the methods described for the keto‐MA variant trans ‐kMA 56.…”

Section: Methodsmentioning

confidence: 99%

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Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern

et al. 2010

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Mycolic acids (MAs) occur in the cell wall of Mycobacterium tuberculosis as variable mixtures of different classes and chain lengths. Here, we address the relationship between the structure and its inflammatory function of this virulence factor using single synthetic MA isomers, differing in oxygenation class and cis- versus α-methyl-trans proximal cyclopropane orientation. Analysis of bronchoalveolar inflammation, lung histopathology and alveolar macrophage transcription revealed a strong dependence on these meromycolic chemistries of mouse pulmonary inflammation in response to intratracheal treatments with MAs. Whereas α-MA was inert, oxygenated methoxy- and keto-MA with cis-cyclopropane stereochemistry elicited solid to mild inflammatory responses respectively. In trans-cyclopropane orientation, methoxy-MA partially lost its inflammatory activity and keto-MA exerted anti-inflammatory alternative activation of alveolar macrophages and counteracted cis-methoxy-MA induced airway inflammation. The differential innate immune activities of MAs demonstrated here, dependent on oxygenation class and cis versus α-methyl-trans cyclopropane chemistry, identify a novel means for M. tuberculosis to steer host immune responses during infection.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern

et al. 2010

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“…Briefly, rhodium-catalyzed cyclopropenation of octyne with ethyl diazoacetate was followed by resolution of the enantiomers via diastereomer formation and chromatography (Liao et al, 2004). The resulting enantiopure cyclopropenes were then converted to the desired enantiomeric fatty acids over several synthetic steps including a Wittig reaction (Coxon et al, 1999) and a diimide reduction (Smit et al, 2008). Diacylglycerol was prepared by epoxide ring opening (Jacobsen et al, 1997) of protected S-glycidol with palmitic acid, followed by esterification of the resulting hydroxyl group with the 9R,10S cyclopropyl fatty acid.…”

Section: Synthesis Of Diptmentioning

confidence: 99%

Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria

Reinink

Buter

Mishra

et al. 2019

Journal of Experimental Medicine

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Salmonella species are among the world’s most prevalent pathogens. Because the cell wall interfaces with the host, we designed a lipidomics approach to reveal pathogen-specific cell wall compounds. Among the molecules differentially expressed between Salmonella Paratyphi and S. Typhi, we focused on lipids that are enriched in S. Typhi, because it causes typhoid fever. We discovered a previously unknown family of trehalose phospholipids, 6,6′-diphosphatidyltrehalose (diPT) and 6-phosphatidyltrehalose (PT). Cardiolipin synthase B (ClsB) is essential for PT and diPT but not for cardiolipin biosynthesis. Chemotyping outperformed clsB homology analysis in evaluating synthesis of diPT. DiPT is restricted to a subset of Gram-negative bacteria: large amounts are produced by S. Typhi, lower amounts by other pathogens, and variable amounts by Escherichia coli strains. DiPT activates Mincle, a macrophage activating receptor that also recognizes mycobacterial cord factor (6,6′-trehalose dimycolate). Thus, Gram-negative bacteria show convergent function with mycobacteria. Overall, we discovered a previously unknown immunostimulant that is selectively expressed among medically important bacterial species.

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“…Minnikin and co-workers reported the synthesis of both enantiopodes of enantiopure lactobacillic acid 4 by bidirectional elaboration of a homo-chiral cyclopropane linchpin, which was derived from lipasemediated desymmetrization of cis-cyclopropane-1,2-dimethanol or by diastereoselective Simmons-Smith cyclopropanation of a D-mannitol-derived alkene. 21,22 Kobayashi and co-workers reported a related approach to both enantiomers of cis-9,10methylenehexadecanoic acid 1 involving bidirectional Wittig extension of an enzymatically-derived homochiral cyclopropaγ-lactone. 16 Manthorpe and co-workers have reported the synthesis of enantiopure 9R,10S-dihydrosterculic acid 3 with the key step involving the Corey-Chaykovsky cyclopropanation of a homochiral alkylidene bis(sulfoxide).…”

Section: Introductionmentioning

confidence: 99%

Total syntheses of cis-cyclopropane fatty acids: dihydromalvalic acid, dihydrosterculic acid, lactobacillic acid, and 9,10-methylenehexadecanoic acid

2014

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cis-Cyclopropane fatty acids (cis-CFAs) are widespread constituents of the seed oils of subtropical plants, membrane components of bacteria and protozoa, and the fats and phospholipids of animals. We describe a systematic approach to the synthesis of enantiomeric pairs of four cis-CFAs: cis-9,10-methylenehexadecanoic acid, lactobacillic acid, dihydromalvalic acid, and dihydrosterculic acid. The approach commences with Rh2(OAc)4-catalyzed cyclopropenation of 1-octyne and 1-decyne, and hinges on the preparative scale chromatographic resolution of racemic 2-alkylcycloprop-2-ene-1-carboxylic acids using a homochiral Evan's auxiliary. Saturation of the individual diastereomeric N-cycloprop-2-ene-1-carbonylacyloxazolidines, followed by elaboration to alkylcyclopropylmethylsulfones, allowed Julia-Kocienski olefination with various ω-aldehyde-esters. Finally, saponification and diimide reduction afforded the individual cis-CFA enantiomers.

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The synthesis of both enantiomers of lactobacillic acid and mycolic acid analogues

Cited by 20 publications

References 17 publications

Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern

Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflammatory pattern

Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria

Total syntheses of cis-cyclopropane fatty acids: dihydromalvalic acid, dihydrosterculic acid, lactobacillic acid, and 9,10-methylenehexadecanoic acid

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