The enantioselective synthesis of the C-4′ acylated 1,4-α,α-manno,manno-disaccharide fragment of mannopeptimycin-E has been achieved in 7 steps from D-tyrosine. The route relies upon diastereoselective palladium-catalyzed glycosylation, diastereoselective reduction and diastereoselective bis-dihydroxylation. The efficiency of the synthesis is demonstrated by the high overall yield (37%) and the preparation of various analogues.The continuing emergence of bacterial resistance to traditional antibiotics has inspired a neverending search for new antibiotics. 1 The five mannopeptimycins (1a-e) were isolated from the fermentation broths of Streptomyces hygroscopicus LL-AC98 and related mutant strains. 2 The key structural features of the mannopeptimycins are a cyclic hexapeptide core with alternating D-and L-amino acids, three of which are rare. Two of the amino acids (β-Dhydroxyenuricididine and D-tyrosine) are glycosylated with mannose sugars. The glycosylated amino acids are an N-glycosylated β-hydroxyenuricididine with an α-mannose, and an Oglycosylated tyrosine with a α-(1,4-linked)-bis-manno-pyranosyl-pyranoside.The unique structure and unprecedented biological activity have inspired both biological 2,3 and synthetic studies 4 from labs at Wyeth pharmaceuticals. Among the mannopeptimycins, mannopeptimycin-E (1e , Scheme 1) was reported as the most active member against methicillin-resistant staphylococci and vancomycin-resistant enterococci (Table 1). 5A particularly interesting aspect of the SAR for the mannopeptimycins is how the specific placement of the isovalerate group on the bis-manno-disaccharide correlates with its antibacterial activity. It has been shown that C-4 isovalerate substitution on the terminal mannose leads to a substantial increase in antibacterial potency. For instance, mannopeptimycins-C and -D, which have C-2 and C-3 isovalerate groups respectively, have reduced activity, whereas mannnopeptimycins-A and -B, which lack isovalerate substitution have even lower activity (Table 1). 5Although the total synthesis of mannopeptimycin has not been reported, Wang et al. have reported a synthesis of cyclic peptides related to mannopeptimycin having a C-4/C-6 acetal as an isovalerate substitute. 4a This work also confirmed the importance of the C-4 isovaleryl group for antibiotic activity. The critical role isovalerate substitution has on the antibacterial activity of the mannopeptimycin-E inspired us to pursue a synthesis of an appropriate Oglycosylated D-tyrosine with C-4 isovalerate substitution (e.g. 2a and 2b , Scheme 1). 6 In addition to our desire to synthesize and test the mannopeptimycin analogues 2a and 2b, we felt that the synthesis of 2a would serve as part of a model study for our synthesis of the natural product. In addition, the preparation of 3b, a fully protected bis-glycosylated tyrosine (Scheme 2), would be of use for the synthesis of mannopeptimycin E. Herein, we report the successful implementation of our palladium-catalyzed glycosylation reaction Our retrosynthetic ana...
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