Synthesis of a Di-Mycoloyl Tri-Arabinofuranosyl Glycerol Fragment of the Mycobacterial Cell Wall, Based on Synthetic Mycolic Acids

Abstract

Fragments of mycobacterial cell walls such as arabinoglycerol mycolate and dimycoloyl diarabinoglycerol, comprising complex mixtures of mycolic acids, have immunostimulatory and antigenic properties. A related di-mycoloyl tri-arabinofuranosyl glycerol fragment has been isolated from cell wall hydrolysates. An effective stereoselective synthesis of tri-arabinofuranosyl glycerol, followed by coupling with stereochemically defined mycolic acids of different structural classes, to provide unique di-mycoloyl tri-arabinofuranosyl glycerols is now described.

Keywords: cell membrane; mycobacteria; mycolic acids; triarabinoglycerol.

Figure 1

Generalised structure of mycolic acids (1), dimycoloyl diarabinoglycerol (DMAG) (2) and dimycoloyl triarabinoglycerol (DMTAG) (3).

Scheme 1

Synthesis of fully protected glycan tri-arabino glycerol (TAG) (6).

Scheme 2

Synthesis of the acceptor (5).

Scheme 3

Synthesis of compound (9). Reagents and conditions: (i) MeONa (1 M), then ethanoic acid (AcOH), 83%; (ii) benzyl bromide (BnBr), NaH, dimethylformamide (DMF), 65%; (iii) tetrabutylammonium fluoride (TBAF), tetrahydrofuran (THF), 87%.

Scheme 4

Synthesis of a model di-behenoyl tri-arabinoglycerol (11, R = H). Reagents and conditions: (i) methanesulfonyl chloride (MsCl), 4-dimethylaminopyridine (DMAP), pyridine, 87%; (ii) CsHCO₃, behenic acid, DMF/THF, 70 °C, (11, R = Bn, 80%); (iii) Pd(OH)₂/C (20%), H₂, 82%.

Scheme 5

Synthesis of dimycoloyl triarabinoglycerol (DMTAG) glycolipids. (i) RCOOH (R’ = TBDMS) (12a–c), 1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide (EDCI), DMAP, CH₂Cl₂ (a: 51%; b: 84%; c: 46%); (ii) TBAF, THF (a 76%; b: 51%; c: 66%); (iii) Pd(OH)₂/C (20%), H₂, CH₃OH:CH₂Cl₂: THF (1:1:1.5), rt, 36 h, (a: 86%; b: 88%; c: 82%).