Tn Antigen Mimics by Ring-Opening of Chiral Cyclic Sulfamidates with Carbohydrate C1-S- and C1-O-Nucleophiles

Abstract

Starting from commercially available ( S)-isoserine and effectively accessible ( S)-α-methylserine, enantiopure cyclic sulfamidates have been prepared as chiral building blocks for the synthesis of various S- and O-glycosylated amino acid derivatives, including unnatural variants of the Tn antigen, through highly chemo-, regio-, and stereoselective nucleophilic ring-opening reactions with carbohydrate C1- S- and C1- O-nucleophiles.

Oxygen by Carbon Replacement at the Glycosidic Linkage Modulates the Sugar Conformation in Tn Antigen Mimics

“…Initially, we synthesized the Tn antigen mimics 2 and 3 through our recently reported strategy involving the ring-opening of chiral cyclic sulfamidates with carbohydrate C1– O -nucleophiles . Thus, starting from effectively accessible ( S )-α-methylserine and commercially available ( S )-isoserine, enantiopure cyclic sulfamidates 8 and 9 were efficiently prepared as chiral building blocks for the synthesis of GalNAc- O -glycosylated amino acids ( S )-α-methylserine and ( S )-isoserine, respectively.…”

“…The synthesis and biological evaluation of analogues of natural carbohydrates and glycopeptides − can contribute to understanding different biochemical processes and provide new candidates for biological targets. We have reported several examples of non-natural Tn antigen mimics − comprising minor structural modifications, some of them being able to imitate the conformational preferences of the natural antigens in solution, enhancing the binding affinity to anti-MUC1 antibodies. Herein, we continue exploring this strategy and report new variants in which the underlying amino acid of the Tn antigen ( 1 ) has been altered and in some cases covalently linked to the carbohydrate to fix the native conformation of the glycosidic linkage. − The explored modifications include the substitution of Thr by α-methylserine (mimic 2 ) ,, or isoserine (mimic 3 ), two compounds already prepared by us but whose conformational analysis has not been accomplished yet.…”

Progress, challenges and future directions of heterocycles as building blocks in iterative methodologies towards sequence-defined oligomers and polymers

“…Unlike aziridines or azetidines, CS reactivity is not predominantly driven by ring strain meaning 5-and 6-membered CSs retain similar reactivity. CS ring opening has been demonstrated with a diverse set of nucleophiles including thiols, 104,105 amines, 106, 107 halides including fluoride, 107,108 and iodide, 109 azide, 106, 107, 110 , thiocyanate, 107 and carbon-centred nucleophiles like organometallics, [111][112][113][114] cyanide, 106 and enolates. 107,115 Trifluorothiomethylation has also been demonstrated.…”

Lanthionine Peptides by S-Alkylation with Substituted Cyclic Sulfamidates Promoted by Activated Molecular Sieves: Effects of the Sulfamidate Structure on the Yield

“…These ring-opening reactions give access to new lanthipeptides incorporating lanthionine mimics based on -methylisoserine (-methylnorlanthionine). 17 The yields of the final lanthipeptides were found to be strongly dependent on the type of protecting group on the sulfamidate carboxylic function. Compounds 1f and 1h, both having methyl ester protection on the sulfamidate carboxyl function, gave high and comparable yields.…”

“…This procedure was shown to proceed with the total inversion of the configuration at the electrophilic carbon, preserving the enantiomeric excess of the starting material. 17 This methodology was demonstrated mostly on (S)-N-Boc isoserine-sulfamidate d, and used 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base to activate the Snucleophiles. Being encouraged by the mild synthetic strategy based on activated molecular sieves for Salkylation with cyclic serine-sulfamidates, 13 we tested such a route to access lanthipeptides incorporating lanthionine mimics featuring isoserine (norlanthionine).…”