Aggregation of a Tetrasaccharide Acceptor Observed by NMR: Synthesis of Pentasaccharide Fragments of the Le^aLe^x Tumor-Associated Hexasaccharide Antigen

Abstract

We report the synthesis of a tetrasaccharide and two pentasaccharide fragments of the Le a

Synthesis of LacNAcLex‐ and DimLex‐BSA Conjugates and Binding to Anti‐Polymeric Lex mAbs

“…The outcome of the one‐step full deprotection of hexasaccharides 34 and 35 in dissolving metal conditions [Na/NH 3 ( l )] which led to a non‐negligible loss of the azide group from the hexyl chain giving hexasaccharide 3 was unexpected. Indeed, while the yields of one‐step deprotection of many such analogs that we have reported, , , , varied from 59 % to 78 %, we had never, until now, isolated the corresponding deaminated oligosaccharides. The structure of the final tetra‐ and pentasaccharides 2 – 4 were confirmed by NMR and HRMS.…”

“…It began with levulinoylation at O‐3 of known 6‐chlorohexyl glycoside 5 with levulinic anhydride that was prepared from levulinic acid as described by Hassner et al Levulinate 6 was obtained in excellent yield and submitted to the acid hydrolysis of the benzylidene acetal (80 % AcOH, 50 °C); the resulting diol 7 was then selectively benzoylated at the primary hydroxyl group with benzoyl chloride and collidine at room temperature. Acceptor 8 , free at O‐4, was obtained in 75 % yield and glycosylated with known trichloroacetimidate donor 9 . It has been well‐documented that glycosylation at O‐4 of N ‐acetylglucosamine was challenging but could be achieved using trichloroacetimidate donors activated with greater than 2 equivalents of BF 3 · Et 2 O at room temperature or 40 °C.…”

“…While tetrasaccharide 25 was set aside for full deprotection, tetrasaccharides 23 , 24 and 26 were treated with hydrazine monoacetate in ethanol to selectively remove the levulinoyl group at O‐3( A ) yielding tetrasaccharide acceptors 27 – 29 in good yields (Scheme ). To prevent aggregation of the acceptors in non‐polar solvents, fucosylation of tetrasaccharides was achieved using known fucosyl donor 30 (4–6 equiv.) activated with copper(II) bromide and tetrabutylammonium bromide in a mixture of DMF and dichloromethane at room temperature.…”

“…With protected tetra‐ and pentasaccharides 25 and 32 – 35 in hand, we embarked on their one‐step full deprotection in dissolving metal conditions using sodium in liquid ammonia at –78 °C, as we have reported before for similar oligosaccharides (Scheme ) , , , ,…”

“…While hexyl glycosides 2 and 3 were obtained in 55–65 % from protected intermediates 25 , 32 or 33 , we observed that the 6‐azidohexyl pentasaccharides 34 and 35 led to the desired 6‐aminohexyl pentasaccharide 4 in mediocre yields (≈ 40 %) while non‐negligible amounts of hexyl glycoside 3 were also isolated (Scheme ). We have employed such one‐step deprotection strategy on numerous occasions, , , and obtained the desired aminated final compounds in acceptable to good yields with no isolation of the corresponding de‐aminated products.…”