Mycolactone

SCHEME 48. Synthesis of the side chains of mycolactones A and via Pd-catalyzed stepwise double substitution... 

Mycolactones A (71) and B are 12-membered ring macrolides produced by a myxobacterium, Mycobacterium ulcerans [89, 90]. M. ulcerans causes Buruli ulcer, a severe human skin disease that occurs primarily in Africa and Australia. Mycolactones are suggested to play a major role in the pathology of the disease... 

A Walk Across Africa with Captain Grant Exploring Mycobacterium ulcerans Infection with Mycolactone Analogs... 

FIGURE 1 Stnicture of mycolactone A/B, a dynamic equilibrium of (at least) two stereoisomers. 

Mycolactone A/B gross structure (Small, 1999) FIGURE 3 Determination of mycolactone structure by Small and Kishi. 

Let us go back in time, more precisely to 2005 at that time, the stereo-stmcture of mycolactone was established and a single total synthesis had been reported by Professor Kishi. But nothing was known about the mode of action of this seductive macrolide, besides the fact that it was a very potent cyto-pathic and immunosuppressive agent. Moreover, the biosynthesis of mycolactone had just been deciphered by the team of Cole (2004) " from the Institut Pasteur (Paris). A blossoming of chemical biology investigatirMis in the field of M. ulcerans infection was just around the comer. 

Sections 2.2 and 2.3 focus on the detailed synthesis of the macrolactonic and southern fragments of mycolactone A/B analogs, and the assembly of all fragments will be discussed next in Section 2.4. 

With efficient access to a simplified macrolactonic core of mycolactone A/B, we proceeded to the union with the northern fragment, following the strategy pioneered by Kishi. Thus, the C13-iodo macrolactone 33 was... 

The synthesis of this simplified macrolactonic fragment of mycolactone A/B in hand, we next turned our attention to the development of a modular synthesis of the Cl -C16 southern fragment of mycolactone A/B. 

Mycolactone E, frog pathogen (M. ulcmans ecovar Uflandii)... 

Mycolactone F, salt-water fish pathogen (M. marinum M)... 

Mycolactone SI, human pathogen (M. ulcerans subsp. shinshuense)... 

FIGURE 4 The structural diversity in the mycolactone family is ctaifined to the southern fragment (always as a mixture of isomers). 

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