Total Synthesis of Enantiopure β-d-Mannosyl Phosphomycoketides from Mycobacterium tuberculosis

Abstract

The first stereoselective total synthesis of a beta-d-mannosyl phosphomycoketide is reported. To introduce the stereogenic centers in the chain, three linear chiral building blocks were prepared using two different asymmetric catalytic conjugate addition protocols. Coupling of the various linear fragments was affected using a Julia-Kocienski sequence. This approach constitutes a general and convergent method for the construction of saturated oligoisoprenoid chains of any length and stereochemistry. In addition, an alternative approach for the formation of the difficult beta-mannosyl phosphate linkage was shown to be successful. Biological evalutation of the all-S compound revealed that its antigenic potency for T cells is identical to that of the natural product. This result implies that the fine structure of the lipid part has a strong influence on biological activity and that the T cell response is discriminating between different stereoisomers.

Phosphoramidite: privilegierte Liganden in der asymmetrischen Katalyse

“…[177] Ein weiteres Beispiel für die Vielseitigkeit dieser katalytischen Methode ist die Totalsynthese von zwei im Mycobacterium tuberculosis natürlich vorkommenden Verbindungen. [178,179] Weiterhin wurden konjugierte Additionen von Dialkylzinkreagentien an cyclische stickstoffhaltige Michael-Akzeptoren wie die Lactame 72 und die Piperidone 74 beschrieben (Schema 21 a und b). [180,181] [183] Die Addition von weniger reaktivem Dimethylzink an die von Chalkon abgeleiteten, a,b-ungesättigten (Pyridyl)sulfonylimine 81 wurde ebenfalls untersucht (Schema 24 a).…”

Biologically active Phytophthora mating hormone prepared by catalytic asymmetric total synthesis

“…Compound 2 may be accessed via the assembly of two fragments 3 and 4 employing a dithiane coupling strategy (27)(28)(29)(30)(31). Both 3 and 4 are available from the ␣,␤-unsaturated thioesters 5 and 6 (11)(12)(13), each with a different alcohol protecting group to allow selective deprotection in later stages of the synthesis.…”

“…In 2005, Qi et al (5) reported the purification of a Phytophthora mating hormone and revealed that the structure consists of an array of 1,5-stereogenic centers. Such structures can in principle be accessed by our recently developed powerful methodology of catalytic enantioselective conjugate addition of Grignard reagents (6)(7)(8)(9)(10)(11)(12)(13)(14) (Fig. 1).…”

“…Recently, we developed a highly enantioselective conjugate addition (CA) of Grignard reagents, in particular MeMgBr, to ␣,␤-unsaturated thioesters catalyzed by a copper bromide complex of Josiphos ligand (Fig. 1B) and applied this methodology in a diastereo-and enantioselective iterative route to deoxypropionate chains (6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Iterative strategies for the synthesis of deoxypropionates

“…Although the Pfaltz group did not describe an iterative approach for the construction of polydeoxypropionates, their findings elegantly demonstrate an approach for the construction of 1,5-polymethyl structures. These occur in polypropionates from Mycobacterium tuberculosis 53 as well as in many isoprenoids.…”