Process for the preparation of regular glycopeptides

A method for producing a glycopeptide of the formula (III):

• wherein
• R1′ is a protected amino group;
• R2′ is —OR7′ wherein R7′ is a hydrogen atom or a residue of a saccharide;
• R3′ is —OR7′ wherein R7′ is a hydrogen atom or a residue of a saccharide;
• R4′ is —CH2OR8′ wherein R8′ is a hydrogen atom or a residue of a saccharide, or R4′ is —CH3;
• R5′ is a hydrogen atom;
• R7 is alanine residue;
• R8 is alanine residue;
• and
• R9 is methyl group;
• said method comprising:
• (a) reacting a fluorinated monosaccharide or a fluorinated oligosaccharide of the formula (I) with L-alanyl-L-threonyl-L-alanine having a C-terminal carboxyl group which is protected by a carboxyl-protecting group and an N-terminal amino group which is protected by an amino-protecting group, for a time and under conditions effective to produce a compound of the formula (II),
• wherein the fluorinated monosaccharide or oligosaccharide of formula (I) is
• wherein
• R1 is an amino group precursor;
• R2 is —OR7′ wherein R7′ is a hydrogen atom, an etheral hydroxyl-protecting group, or a residue of a saccharide;
• R3 is —OR7′ wherein R7′ is a hydrogen atom, an etheral hydroxyl-protecting group, or a residue of a saccharide;
• R4 is —CH2OR8′ wherein R8′ is a hydrogen atom, an etheral hydroxyl-protecting group, or a residue of a saccharide, or R4 is —CH3;
• R5 is a hydrogen atom;
• and wherein the compound of formula (II) is
• wherein R1, R2, R3, R4, R5, R7, R8 and R9 are the same as defined above,
• R10 is said amino-protecting group;
• R11 is said carboxyl-protecting group;
• and
• wherein both said amino-protecting group and said carboxy-protecting group are removable by hydrogenation;
• (b) converting the amino group precursor of R1 to a protected amino group,
• (c) hydrogenating the compound of the formula (II) for a time and under conditions effective to produce the glycopeptide of the formula (III);
• and
• (d) isolating the glycopeptide of the formula (III).

A method for producing a sequential glycopeptide of the formula (IV):

• wherein
• R1′ is —OH or a protected amino group;
• R2′ is —OR7′ wherein R7′ is a hydrogen atom or a residue of a saccharide;
• R3′ is —OR7′ wherein R7′ is a hydrogen atom or a residue of a saccharide;
• R4′ is —CH2OR8′ wherein R8′ is a hydrogen atom or a residue of a saccharide, or R4′ is —CH3;
• R5′ is a hydrogen atom;
• R7 is alanine residue;
• R8 is alanine residue;
• R9 is methyl group;
• and
• n is an integer of 2 to 20;
• said method comprising:
• (a) reacting a fluorinated monosaccharide or a fluorinated oligosaccharide of the formula (I) with L-alanyl-L-threonyl-L-alanine having a C-terminal carboxyl group which is protected by a carboxyl-protecting group and an N-terminal amino group which is protected by an amino-protecting group, for a time and under conditions effective to produce a compound of the formula (II),
• wherein the fluorinated monosaccharide or oligosaccharide of formula (I) is
• wherein
• R1 is —OR6 wherein R6 is a hydrogen atom or an etheral hydroxyl-protecting group, or an amino group precursor;
• R2 is —OR7′ wherein R7′ is a hydrogen atom, an etheral hydroxyl-protecting group or a residue of a saccharide;
• R3 is —OR7′ wherein R7′ is a hydrogen atom, an etheral hydroxyl-protecting group or a residue of a saccharide;
• R4 is —CH2OR8′ wherein R8′ is a hydrogen atom, an etheral hydroxyl-protecting group, or a residue of a saccharide, or R4 is —CH3;
• R5 is a hydrogen atom;
• and wherein the compound of formula (II) is
• wherein R1, R2, R3, R4, R5, R7, R7 and R9 are the same as defined above,
• R10 is said amino-protecting group;
• R11 is said carboxyl-protecting group;
• and
• wherein both said amino-protecting group and said carboxyl-protecting group are removable by hydrogenation;
• (b) optionally converting an amino group precursor of R1 to a protected amino group,
• (c) hydrogenating the compound of the formula (II) for a time and under conditions effective to produce a glycopeptide of the formula (III):
• wherein
• R1′ is —OH or a protected amino group;
• R2′ is —OR7′ wherein R7′ is a hydrogen atom or a residue of a saccharide;
• R3′ is —OR7′ wherein R7′ is a hydrogen atom or a residue of a saccharide;
• R4′ is —CH2OR8′ wherein R′ is a hydrogen atom or a residue of a saccharide, or R4′ is —CH3;
• R5′ is a hydrogen atom;
• R7 is alanine residue;
• R8 is alanine residue;
• and
• R9 is methyl group;
• (d) subjecting a plurality of glycopeptides of the formula (III) to a polycondensation reaction in the presence of a condensation agent selected from the group consisting of an organic phosphorus compound, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and 1-isobutyl-2-isobutyl-1,2-dihydroquinoline;
• and
• (e) isolating the sequential glycopeptide of the formula (IV).