A divergent and highly stereoselective route to eleven glycosylated methymycin analogues has been developed. The key to the success of this method was the iterative use of the Pd-catalyzed glycosylation reaction and post-glycosylation transformation. This unique application of Pd-catalyzed glycosylation demonstrates the breath of α/β-& D/L-glycosylation of macrolides that can be efficiently prepared using a de novo asymmetric approach to the carbohydrate portion.

A highly stereoselective synthesis of L-2-deoxy-β-ribo-hexopyranosyl nucleosides from 6-chloropurine and Boc-protected pyranone has been developed. Our approach relies on the iterative application of a palladium catalyzed N-glycosylation, diastereoselective reduction and reductive 1,3-transposition. This strategy is amenable to prepare various natural and unnatural hexopyranosyl nucleosides analogues.The hexopyranosyl nucleosides make up a large and varied class of natural products (e.g. blasticidin, 1 gougerotin, 2 hikizimycin, 3 mildiomycin, 4 the bagougeramines, 5 SF-2140, 6 the pentopyranines, 7 and miharamycin 8 ). In addition to displaying intriguing structures, they also possess distinct biological activities. 9 Inspired by these natural products, chemists have made two hexopyranosyl nucleosides 2-deoxy-β-D-ribo-hexopyranose adenosine (1) 10 and 2,3-dideoxy-β-D-ribo-hexopyranose adenosine (2). 11 These homologous nucleosides of adenosine and deoxy-adenosine possess obvious structural and configurational similarities to the corresponding ribofuranose adenosines 3 and 4 (Figure 1). Biological studies of these ringexpanded analogues (1 and 2) have led to the discovery of several pyrano-nucleotide analogues with both antitumor and antiviral activity. 10,11,12 The interest in analogs of 3 and 4 has also led to the development of many novel nucleoside structures with anticancer and/or antiviral activity. 12While there has been significant synthetic effort toward the synthesis of adenosine analogs, 9 we were interested in preparing pyrano-analogues of this class of compounds from an achiral starting material using enantioselective catalysis to set the asymmetry (de novo synthesis). In addition, we were interested in a synthesis that allows for the diastereoselective installation of the base at C-1. Our retrosynthetic analysis of 1 and 2 was particularly influenced by Trost's de novo synthesis of the nucleosides. 13As part of our efforts working toward the de novo synthesis of carbohydrates, we discovered a palladium catalyzed glycosylation reaction that selectively converts 2-substituted 6-tbutoxycarboxy-2H-pyran-3(6H)-ones into 2-substituted 6-alkoxy-2H-pyran-3(6H)-ones with complete retention of configuration. 14 This methodology has been extended toward the preparation of several natural/unnatural mono-, di-and trisaccharides. 15 To test the breadth of this methodology, we set out to prepare various analogs of pyranose adenosines (1 and 2). To accomplish this goal, we needed to extend the palladium glycosylation reaction to nitrogen nucleophiles (e.g. benzimidazole and purines). 16 Herein we describe our successful efforts to prepare the homo-adenosine analogues 1 and 2. 17We envisioned that both the homo-adenosine 1 and the deoxy-homo-adenosine 2 could be prepared from the β-pyranone 7, which in turn could be prepared by a palladium catalyzed glycosylation of the β-Boc-pyranone 9 with chloropurine 8 (Scheme 1). 18 A diastereoselective reduction of 7 should provide 6, which could be converted into 2 b...

Two C4' amido disaccharide analogues of mannopeptimycin-E were synthesized via an iterative palladium glycosylation sequence. The stereoselective synthesis of the C4' acylated 1,4-alpha,alpha-manno,manno-amido disaccharide has been achieved in ten steps from a protected d-tyrosine. The path relies upon a regio- and diastereoselective palladium-catalyzed azide substitution reaction. The competence of the synthesis is demonstrated by the good overall yield (21%) from protected tyrosine.