The natural all d- and/or unnatural all l-1,4- and 1,6-oligosaccharides were synthesized from furan alcohols using a palladium-catalyzed glycosylation reaction. The 1,4- and 1,6-alpha-manno-disaccharides were achieved in seven total steps starting from chiral furan alcohols. Similarly, 1,4- and 1,6-alpha-manno-trisaccharides were also synthesized in nine total steps. Key to the overall efficiency of this process was the use of highly diastereoselective palladium-catalyzed glycosylations, reductions, and dihydroxylations.

A highly stereoselective and sterospecific palladium-catalyzed glycosylation reaction of a variety of alcohols is reported. The reaction selectively converts alpha-2-substituted 6-carboxy-2H-pyran-3(6H)-ones into alpha-2-substituted 6-alkoxy-2H-pyran-3(6H)-ones with complete retention of configuration and similarly converts the pyranones with beta-carboxy groups into pyranones with beta-alkoxy groups. The reaction works equally well with both amino acid- and carbohydrate-based alcohols. To demonstrate the utility of this process for carbohydrate chemistry several of the products were selectively converted into alpha-manno-pyranosides in two additional steps. Because the 2-substituted 6-carboxy-2H-pyran-3(6H)-ones are prepared by asymmetric synthesis, this reaction can be used for the preparation of either d- or l-pyranones.

Oligosaccharide synthesis is hindered by the need for multiple steps as well as numerous selective protections and deprotections. Herein we report a highly efficient de novo route to various oligosaccharide motifs, of use for biological and medicinal structure activity studies. The key to the overall efficiency is the judicious use of asymmetric catalysis and synthetic design. These green principles include the bidirectional use of highly stereoselective catalysis (Pd(0)-glycosylation/post-glycosylation). In addition, the chemoselective use of C-C and C-O π-bonds functionality, as atom-less protecting groups as well as an anomeric directing group (via a Pd-π-allyl), highlights the atom economical aspects of the route to a divergent set of natural and unnatural oligosaccharides (i.e., various D-/L-diastereomers of oligosaccharide as well as deoxysugars which lack C-2 anomeric directing groups). For example, in only 12 steps, the construction of a highly branched hepta-saccharide with 35 stereocenters was accomplished from an achiral acylfuran.

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...

No abstract