Methods for the synthesis of two or more dicarba bridges in organic compounds

A method for the synthesis of a peptide with two intramolecular dicarba bridges, and a disulfide bridge, the method comprising:

• (a) providing a first peptide comprising a series of amino acids attached to a solid support, wherein two amino acids comprise sidechains with a first pair of complementary metathesisable groups and two amino acids comprise sidechains with a second pair of blocked complementary metathesisable groups, and two amino acids in the peptide are protected cysteine residues;
• (b) subjecting the peptide to cross-metathesis to form a peptide with an unsaturated dicarba bridge between the amino acids bearing the first pair of complementary metathesisable groups;
• (c) unblocking the second pair of complementary metathesisable groups,
• (d) subjecting the peptide to cross-metathesis to form a peptide with an unsaturated dicarba bridge between the amino acids bearing the second pair of complementary metathesisable groups, to form a dicarba bridge between the amino acids that bore the second metathesisable groups, and
• (e) deprotecting the cysteine residues and oxidising the cysteine residues to form a disulfide bridge.

A method for the synthesis of a peptide with one intramolecular dicarba bridge, and a second dicarba bridge which is an intermolecular, the method comprising:

• (a) providing a first peptide comprising a series of amino acids attached to a solid support, wherein two amino acids comprise sidechains with a first pair of complementary metathesisable groups which may be blocked or unblocked, and one amino acid comprises a sidechain with a second metathesisable group which may be blocked or unblocked, with the proviso that the metathesisable groups out of at least one of the first or the second metathesisable groups are blocked;
• (b) unblocking the first pair of complementary metathesisable groups, if said groups are blocked and subjecting the peptide to cross-metathesis to form a peptide with an unsaturated dicarba bridge between the amino acids bearing the first pair of complementary metathesisable groups, to form a peptide with an intramolecular dicarba bridge, and
• (c) contacting the first peptide with a second peptide comprising one amino acid with a metathesisable group complementary to the second metathesisable group on the first peptide;
• (d) unblocking the second complementary metathesisable groups, if the second metathesisable groups are blocked;
• and (e) subjecting the peptide to cross-metathesis to form a peptide with an unsaturated dicarba bridge between the amino acids bearing the second pair of complementary metathesisable groups, to form a dicarba bridge between the amino acids that bore the second metathesisable groups,
• wherein steps (b) and (c) are performed in either order, so as to form a peptide with an intermolecular bridge and an intramolecular bridge.

A method for the synthesis of a peptide with one intramolecular dicarba bridge, an intermolecular dicarba bridge, and a disulfide bridge, the method comprising:

• (a) providing a first peptide comprising a series of amino acids attached to a solid support, wherein two amino acids comprise sidechains with a first pair of complementary metathesisable groups which may be blocked or unblocked, and one amino acid comprises a sidechain with a second metathesisable group which may be blocked or unblocked, with the proviso that the metathesisable groups out of at least one of the first or the second metathesisable groups are blocked;
• (b) unblocking the first pair of complementary metathesisable groups, if said groups are blocked and subjecting the peptide to cross-metathesis to form a peptide with an unsaturated dicarba bridge between the amino acids bearing the first pair of complementary metathesisable groups, to form a peptide with an intramolecular dicarba bridge;
• (c) contacting the first peptide with a second peptide comprising one amino acid with a metathesisable group complementary to the second metathesisable group on the first peptide;
• (d) unblocking the second complementary metathesisable groups, if the second metathesisable groups are blocked;
• and
• (e) subjecting the peptide to cross-metathesis to form a peptide with an unsaturated dicarba bridge between the amino acids bearing the second pair of complementary metathesisable groups, to form a dicarba bridge between the amino acids that bore the second metathesisable groups,
• wherein steps (b) and (c) are performed in either order, so as to form a peptide with an intermolecular bridge and an intramolecular bridge, and
• wherein the first peptide, or the combination of the first peptide and the second peptide, comprises a pair of protected cysteines, and the process further comprises deprotecting the cysteine residues and oxidising the cysteine residues to form a disulfide bridge.

A method for the synthesis of a peptide with three intramolecular bridges, the method comprising:

• (a) providing a first peptide comprising a series of amino acids attached to a solid support, wherein two amino acids comprise sidechains with a first pair of complementary metathesisable groups, two amino acids comprise sidechains with a second pair of blocked complementary metathesisable groups and two amino acids comprise sidechains with a third pair of blocked complementary metathesisable groups;
• (b) subjecting the peptide to cross-metathesis under microwave radiation conditions to form a peptide with an unsaturated dicarba bridge between the amino acids bearing the first pair of complementary metathesisable groups;
• (c) optionally subjecting the unsaturated dicarba bridge to hydrogenation (suitably homogeneous hydrogenation);
• (d) unblocking the second pair of complementary metathesisable groups;
• (e) subjecting the peptide to cross-metathesis to form a peptide with an unsaturated dicarba bridge between the amino acids that bore the second pair of complementary metathesisable groups;
• (f) optionally subjecting the unsaturated dicarba bridge to hydrogenation (suitably homogeneous hydrogenation);
• (g) unblocking the third pair of complementary metathesisable groups;
• (h) subjecting the peptide to cross-metathesis to form a peptide with an unsaturated dicarba bridge between the amino acids that bore the third pair of complementary metathesisable groups;
• and
• (i) optionally subjecting the unsaturated dicarba bridge to hydrogenation (suitably homogeneous hydrogenation).