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Poly-N-acetyl lactosamines (polyLacNAc) are common structural motifs of N- and O-linked glycan, glycosphingolipids and human milk oligosaccharides. They can be branched by the addition of β1,6-linked N-acetyl-glucosamine (GlcNAc) moieties to internal galactoside (Gal) residues by the I-branching enzyme beta-1,6-N-acetylglucosaminyltransferase 2 (GCNT2). I-branching has been implicated in many biological processes and is also associated with various diseases such as cancer progression. Currently, there is a lack of methods that can install, in a regioselective manner, I-branches and allows the preparation of isomeric poly-LacNAc derivatives. Here, we described a chemo-enzymatic strategy that addresses this deficiency and is based on the enzymatic assembly of an oligo-LacNAc chain that at specific positions is modified by a GlcNTFA moiety. Replacement of the trifluoroacetyl (TFA) moiety by tert-butyloxycarbonyl (Boc) gives compounds in which the galactoside at the proximal site is blocked from modification by GCNT2. After elaboration of the antennae, the Boc group can be removed, and the resulting amine acetylated to give natural I-branched structures. It is also shown that fucosides can function as a traceless blocking group that can provide complementary I-branched structures from a single precursor. The methodology made it possible to synthesize a library of polyLacNAc chains having various topologies., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)