Sequential One-Pot Glycosidations Catalytically Promoted: Unprecedented Strategy in Oligosaccharide Synthesis for the Straightforward Assemblage of the Antitumor PI-88 Pentasaccharide

Abstract

The pentasaccharide sequence of the most active components of the antitumor drug PI-88, currently in phase II clinical trial, has been rapidly assembled in high overall yield and in only three steps starting from three monosaccharide building blocks. The procedure takes advantage of the first reported strategy of sequential one-pot glycosidations conducted exclusively under catalytic activation. In addition, the procedure relies only on shelf-stable and mild promoters such as Yb(OTf)(3) and Bi(OTf)(3).

One‐Pot Catalytic Glycosidation/Fmoc Removal – An Iterable Sequence for Straightforward Assembly of Oligosaccharides Related to HIV gp120

“…This we initially allylated at O-3 and per-O-benzylated to give 5 as previously reported. [8] Deallylation of 5 smoothly afforded acceptor 4 (Scheme 1). We prepared 3 from intermediate 6 (Scheme 2), obtained by a previously described one-pot sequence.…”

“…We prepared 3 from intermediate 6 (Scheme 2), obtained by a previously described one-pot sequence. [8,18] We submitted ortho ester 6 to an acid-promoted rearrangement in the presence of allyl alcohol to give 7, which we directly submitted to 2-O deacetylation and Fmoc protection to give 8 in 62 % yield over three steps. Sequential anomeric deallylation and installation of the trifluoroacetimidate [19] leaving group completed the preparation of 3 (90 % yield over two steps).…”

“…[8,14] In a preliminary screening, the use of the former binary mixture for the coupling of 3 with a variety of secondary acceptors provided significant amounts of β-linked glycosides, in spite of the expected participation effect of the 2-O-Fmoc group. Instead, we observed the best result with the ternary solvent mixture (toluene/Et 2 O/diox-ane), and the one-pot sequence in Scheme 3 afforded essentially pure 9 in almost 90 % yield after chromatographic purification.…”

“…[6] In this regard, we have very recently reported the first examples of one-pot, multiple glycosidations exclusively relying on catalytic conditions for donor activation as well as on the use of experimentally convenient, moisture-stable promoters. [7,8] With few exceptions, the sequential glycosidations so far described involve the elongation of the oligomer starting from the nonreducing terminus of the target. However, with the exception of the above-mentioned preactivation strategy, the success of the elongation is critically dependent on the availability of a set of glycosyl donors displaying well-differentiated reactivities.…”

“…By a similar approach, Fmoc was removed in situ from oligosaccharide intermediates generated by electrochemical glycosidations. [13] In this paper, we wish to describe the effective application of Fmoc as a transient group in an iterable sequence for solution oligosaccharide synthesis based on the Bi(OTf) 3 catalyzed activation [8,14] of glycosyl trihaloacetimidates. The devised strategy has been targeted to the rapid assembly of two biologically relevant targets, the protected mannose tetrasaccharide 1 and the branched pentasaccharide 2, both corresponding to moieties incorporated into HIV glycoprotein gp120 (Figure 1).…”