The Synthesis of Single Enantiomers of α-Mycolic Acids of Mycobacterium­ tuberculosis and Related Organisms, with Alternative­ Cyclopropane Stereochemistries

An iterative Ni-catalyzed C(sp 3 )ÀC(sp 3 ) cross-coupling reaction of a novel cis-cyclopropane containing bifunctional building blocks with alkyl halides and alkyl Grignard reagents enabled the introduction of a cyclopropane ring into the desired position(s) of saturated carbon frameworks, providing a straightforward synthetic route to cyclopropane fatty acids. The present method creates a direct route for the construction of saturated carbon frameworks, and can avoid the tedious multistep operations based on unsaturated functional group manipulations that are often employed in conventional synthetic routes. This method could be applicable to the synthesis of trans-cyclopropane fatty acids and enantioenriched cyclopropane fatty acids. Formal synthesis of a-mycolic acid was achieved by the C(sp 3 )ÀC(sp 3 ) cross-coupling reaction of cyclopropane-containing bifunctional building blocks. Scheme 2. Synthetic routes of alkyl chains including a cyclopropane ring. Scheme 3. Synthesis of CFAs using a cyclopropane-containing building block.Scheme 4. Synthesis of cis-cyclopropane-containing building block 7.UPDATES

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Synthesis of Cyclopropane Fatty Acids by C(sp³)−C(sp³) Cross‐Coupling Reaction and Formal Synthesis of α‐Mycolic Acid

Iwasaki

Terahigashi

Wang

et al. 2018

Adv Synth Catal

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Revealing solvent-dependent folding behavior of mycolic acids from Mycobacterium tuberculosis by advanced simulation analysis

et al. 2019

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Mycobacterium tuberculosis remains a persistent pathogen, partly due to its lipid rich cell wall, of which mycolic acids (MAs) are a major component. The fluidity and conformational flexibilities of different MAs in the bacterial cell wall significantly influence its properties, function, and observed pathogenicity; thus, a proper conformational description of different MAs in different environments (e.g., in vacuum, in solution, in monolayers) can inform about their potential role in the complex setup of the bacterial cell wall. Previously, we have shown that molecular dynamics (MD) simulations of MA folding in vacuo can be used to characterize MA conformers in seven groupings relating to bending at the functional groups (W, U and Z-conformations). Providing a new OPLS-based forcefield parameterization for the critical cyclopropyl group of MAs and extensive simulations in explicit solvents (TIP4P water, hexane), we now present a more complete picture of MA folding properties together with improved simulation analysis techniques. We show that the 'WUZ' distance-based analysis can be used to pinpoint conformers with hairpin bends at the functional groups, with these conformers constituting only a fraction of accessible conformations. Applying principle component analysis (PCA) and refinement using free energy landscapes (FELs), we are able to discriminate a complete and unique set of conformational preferences for representative alpha-, methoxy-and keto-MAs, with overall preference for folded conformations. A control backbone-MA without any mero-chain functional groups showed significantly less folding in the mero-chain, confirming the role of functionalization in directing folding. Keto-MA showed the highest percentage of WUZ-type conformations and, in particular, a tendency to fold at its alpha-methyl trans-cyclopropane group, in agreement with results from Villeneuve et al. MAs demonstrate similar folding in vacuum and water, with a majority of folded conformations around the W-conformation, although the molecules are more flexible in vacuum than in water. Exchange between conformations, with a disperse distribution that includes unfolded conformers, is common in hexane for all MAs, although with more organization for Keto-MA. Globular, folded conformations are newly defined and may be specifically relevant in biofilms.

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Total synthesis of naturally occurring chiral cyclopropane fatty acids and related compounds

Inuki

Fujimoto

2019

Tetrahedron Letters

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The Synthesis of Single Enantiomers of α-Mycolic Acids of Mycobacterium tuberculosis and Related Organisms, with Alternative Cyclopropane Stereochemistries

Abstract: We report the synthesis of three stereoisomers of a mycolic acid from Mycobacterium tuberculosis containing a di-cis-cyclopropane and of two stereoisomers of a mycolic acid containing a proximal trans-cyclopropane and a distal cis-cyclopropane.

Cited by 4 publications

References 38 publications

Synthesis of Cyclopropane Fatty Acids by C(sp³)−C(sp³) Cross‐Coupling Reaction and Formal Synthesis of α‐Mycolic Acid

Synthesis of Cyclopropane Fatty Acids by C(sp³)−C(sp³) Cross‐Coupling Reaction and Formal Synthesis of α‐Mycolic Acid

Revealing solvent-dependent folding behavior of mycolic acids from Mycobacterium tuberculosis by advanced simulation analysis

Total synthesis of naturally occurring chiral cyclopropane fatty acids and related compounds

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The Synthesis of Single Enantiomers of α-Mycolic Acids of Mycobacterium­ tuberculosis and Related Organisms, with Alternative­ Cyclopropane Stereochemistries

Abstract: We report the synthesis of three stereoisomers of a mycolic acid from Mycobacterium tuberculosis containing a di-cis-cyclopropane and of two stereoisomers of a mycolic acid containing a proximal trans-cyclopropane and a distal cis-cyclopropane.

Cited by 4 publications

References 38 publications

Synthesis of Cyclopropane Fatty Acids by C(sp3)−C(sp3) Cross‐Coupling Reaction and Formal Synthesis of α‐Mycolic Acid

Synthesis of Cyclopropane Fatty Acids by C(sp3)−C(sp3) Cross‐Coupling Reaction and Formal Synthesis of α‐Mycolic Acid

Revealing solvent-dependent folding behavior of mycolic acids from Mycobacterium tuberculosis by advanced simulation analysis

Total synthesis of naturally occurring chiral cyclopropane fatty acids and related compounds

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Product

Resources

About

The Synthesis of Single Enantiomers of α-Mycolic Acids of Mycobacterium tuberculosis and Related Organisms, with Alternative Cyclopropane Stereochemistries

Synthesis of Cyclopropane Fatty Acids by C(sp³)−C(sp³) Cross‐Coupling Reaction and Formal Synthesis of α‐Mycolic Acid

Synthesis of Cyclopropane Fatty Acids by C(sp³)−C(sp³) Cross‐Coupling Reaction and Formal Synthesis of α‐Mycolic Acid