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

Abstract

Described herein are methods for forming two or more dicarba bridges, as well as new compounds containing dicarba bridges.

What is claimed is: 
     
         1 . A method for synthesizing an organic compound with two or more dicarba bridges, the method comprising:
 (a) providing one or more reactable organic compounds having, within a single compound or between the one or more compounds (i) a first pair of complementary metathesisable groups that are unblocked, (ii) a second pair of complementary metathesisable groups that are blocked but can be unblocked by an unblocking reaction or series of reactions specific to the second pair, and (iii) optionally, one or more further pairs of complementary methathesisable groups that are blocked but can be unblocked by an unblocking reaction or series of reactions specific to each further pair;   (b) subjecting the reactable organic compound or compounds to cross-metathesis to form an organic compound with an unsaturated dicarba bridge across the first pair of complementary metathesisable groups, without cross-metathesis between the pair or pairs of blocked complementary metathesisable groups;   (c) subjecting the second pair of complementary metathesisable groups to the unblocking reaction or series of reactions specific to the second pair;   (d) subjecting the second pair of complementary metathesisable groups to cross-metathesis to form an organic compound with an unsaturated dicarba bridge across the second pair of complementary metathesisable groups, without cross-methathesis between any pair or pairs of complementary methathesisable groups that remain blocked; and   (e) if any complementary metathesisable groups remain, subjecting those groups to unblocking reactions specific to those pairs, followed by cross metathesis.   
     
     
         2 . The method of  claim 1 , comprising hydrogenation of one or more of the unsaturated dicarba bridges formed by cross-metathesis. 
     
     
         3 . The method of  claim 1 , further comprising subjecting the unsaturated dicarba bridge formed between the first pair of complementary metathesisable groups to hydrogenation and subjecting the unsaturated dicarba bridge formed between the second pair of complementary metathesisable groups to hydrogenation, wherein each hydrogenation is performed separately or at the same time. 
     
     
         4 . The method of  claim 1 , wherein conducting one or each of the cross-metathesis reactions for forming a dicarba bridge is conducted under microwave radiation conditions. 
     
     
         5 . The method of  claim 1 , wherein the complementary metathesisable groups of the first pair of complementary metathesisable groups are each independently selected from the group consisting of olefins comprising the portion ═CH 2  and monosubstituted olefins comprising the group ═CHR 5 , wherein R 5  is alkyl or an alkyl substituted by a polar functional group. 
     
     
         6 . The method of  claim 1 , wherein the blocking group of the second pair of complementary metathesisable groups is a steric blocking group, and the unblocking reaction comprises removal of the steric blocking group or conversion of the steric blocking group to a group that is cross-metathesisable. 
     
     
         7 . The method of  claim 6 , wherein the steric blocking group comprises a 1,1-dialkylated olefin. 
     
     
         8 . The method of  claim 1 , wherein the unblocking reaction or series of reactions specific to the second pair of complementary metathesisable groups comprises cross-metathesis with a disposable olefin. 
     
     
         9 . The method of  claim 8 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with disposable olefin that is a mono-substituted ethylene or a 1,2-disubstituted ethylene. 
     
     
         10 . The method of  claim 9 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with a disposable olefin comprising a polar functional group. 
     
     
         11 . The method of  claim 1 , wherein the reactable organic compound comprises a third pair of complementary methathesisable groups that are blocked and can be unblocked by an unblocking reaction or series of reactions specific to the third pair, and the method comprises subjecting the third pair of complementary metathesisable groups to unblocking reactions specific to those pairs, followed by cross metathesis. 
     
     
         12 . The method of  claim 11 , wherein the blocking group of the third pair of complementary metathesisable groups comprises an electronic blocking group, and the unblocking reactions comprise conversion of the electronic steric blocking group to a group that is cross-metathesisable. 
     
     
         13 . The method of  claim 12 , wherein the electronic blocking group comprises a diblocked conjugated diene, and the unblocking reaction comprises subjecting the blocked third pair of complementary metathesisable groups to asymmetric hydrogenation to regioselectively, stereoselectively and chemoselectively hydrogenate one of the diene double bonds to leave a sterically-blocked double bond, followed by cross-metathesis with a disposable olefin to effect removal of the steric blocking groups on the remaining double bond, to yield unblocked complementary metathesisable groups. 
     
     
         14 . The method of  claim 12 , wherein the electronic blocking group comprises
 ═CH—CH═CR 3 R 4 , wherein R 3  and R 4  are each alkyl, and the unblocking reaction comprises hydrogenation of this group to ═CH—CH 2 —CHR 3 R 4 , followed by cross-metathesis with a disposable olefin to yield the unblocked group ═CHR 5 , wherein R 5  is alkyl or an alkyl substituted by a polar functional group.   
     
     
         15 . The method of  claim 1 , wherein the reactable organic compound, or one of the reactable organic compounds, is attached to a solid support during the cross-metathesis of the complementary metathesisable groups. 
     
     
         16 . The method of  claim 15 , wherein the loading of the reactable organic compound on the solid support is at least 0.2 mmol/g. 
     
     
         17 . The method of  claim 15 , wherein the loading of the reactable organic compound on the solid support is at least 0.5 mmol/g. 
     
     
         18 . The method of  claim 15 , wherein each cross-metathesis is performed using a cross-metathesis catalyst, and each cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst. 
     
     
         19 . The method of  claim 18 , wherein the coordinating solvent is an alcohol. 
     
     
         20 . The method of  claim 18 , wherein the coordinating solvent is used in an amount of about 1-30% by volume, with respect to the total solvent combination. 
     
     
         21 . The method of  claim 15 , wherein the reactable organic compound is a peptide. 
     
     
         22 . The method of  claim 21 , wherein the organic compound with two or more dicarba bridges prepared by the method is a peptidomimetic. 
     
     
         23 . The method of  claim 21 , wherein the organic compound with two or more dicarba bridges prepared by the method is a pseudopeptide. 
     
     
         24 . A method for the synthesis of a peptide with two intramolecular dicarba 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 and two amino acids comprise sidechains with a second pair of blocked complementary metathesisable groups;   (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; and   (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.   
     
     
         25 . The method of  claim 24 , wherein two amino acids in the peptide are protected cysteine residues, and the method comprises deprotecting the cysteine residues and oxidising the cysteine residues to form a disulfide bridge. 
     
     
         26 . The method of  claim 24 , wherein one or both of the cross-metathesis steps is followed by a hydrogenation to form a saturated dicarba bridge between the amino acids that bore the complementary metathesisable groups. 
     
     
         27 . The method of  claim 24 , wherein the amino acids that bear the first pair of complementary metathesisable groups are selected from allyl glycine and crotyl glycine, or a combination thereof. 
     
     
         28 . The method of  claim 24 , wherein the amino acids bearing the blocked complementary metathesisable groups of the second pair of complementary metathesisable groups are prenyl glycine or protected prenyl glycine, and the reaction to unblock the blocked metathesisable groups of the second pair of complementary metathesisable groups comprises cross-metathesis with a disposable olefin. 
     
     
         29 . The method of  claim 28 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with a mono-substituted ethylene or a 1,2-disibstituted ethylene. 
     
     
         30 . The method of  claim 29 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with disposable olefin comprising a polar functional group. 
     
     
         31 . The method of  claim 24 , wherein the cross-metathesis of the first and/or the second complementary metathesisable groups is conducted under microwave radiation conditions. 
     
     
         32 . The method of  claim 24 , wherein the cross-metathesis is performed using a cross-metathesis catalyst, and the cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst. 
     
     
         33 . The method of  claim 32 , wherein the cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst which is an alcohol. 
     
     
         34 . The method of  claim 32 , wherein the cross-metathesis is performed in a solvent combination containing about 1-30% of the coordinating solvent by volume, with respect to the total solvent combination. 
     
     
         35 . The method of  claim 24 , wherein the peptide is attached to a solid support during the cross-metathesis of the complementary metathesisable groups and the loading of peptide on the solid support is at least 0.2 mmol/g. 
     
     
         36 . 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.   
     
     
         37 . The method of  claim 36 , wherein one or both of the cross-metathesis steps is followed by a hydrogenation to form a saturated dicarba bridge between the amino acids that bore the complementary metathesisable groups. 
     
     
         38 . The method of  claim 36 , wherein the amino acids that bear the first pair of complementary metathesisable groups are selected from allyl glycine and crotyl glycine, or a combination thereof. 
     
     
         39 . The method of  claim 36 , wherein the amino acids bearing the blocked complementary metathesisable groups of the second pair of complementary metathesisable groups are prenyl glycine or protected prenyl glycine, and the reaction to unblock the blocked metathesisable groups of the second pair of complementary metathesisable groups comprises cross-metathesis with a disposable olefin. 
     
     
         40 . The method of  claim 39 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with a mono-substituted ethylene or a 1,2-disibstituted ethylene. 
     
     
         41 . The method of  claim 40 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with disposable olefin comprising a polar functional group. 
     
     
         42 . The method of  claim 36 , wherein the cross-metathesis of the first and/or the second complementary metathesisable groups is conducted under microwave radiation conditions. 
     
     
         43 . The method of  claim 36 , wherein the cross-metathesis is performed using a cross-metathesis catalyst, and the cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst. 
     
     
         44 . The method of  claim 43 , wherein the cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst which is an alcohol. 
     
     
         45 . The method of  claim 43 , wherein the cross-metathesis is performed in a solvent combination containing about 1-30% of the coordinating solvent by volume, with respect to the total solvent combination. 
     
     
         46 . The method of  claim 36 , wherein the loading of peptide on the solid support is at least 0.2 mmol/g. 
     
     
         47 . 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.   
     
     
         48 . The method of  claim 47 , 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. 
     
     
         49 . The method of  claim 47 , wherein one or both of the cross-metathesis steps is followed by a hydrogenation to form a saturated dicarba bridge between the amino acids that bore the complementary metathesisable groups. 
     
     
         50 . The method of  claim 47 , wherein the amino acids that bear the first pair of complementary metathesisable groups are selected from allyl glycine and crotyl glycine, or a combination thereof. 
     
     
         51 . The method of  claim 47 , wherein the amino acids bearing the blocked complementary metathesisable groups of the second pair of complementary metathesisable groups are prenyl glycine or protected prenyl glycine, and the reaction to unblock the blocked metathesisable groups of the second pair of complementary metathesisable groups comprises cross-metathesis with a disposable olefin. 
     
     
         52 . The method of  claim 51 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with a mono-substituted ethylene or a 1,2-disibstituted ethylene. 
     
     
         53 . The method of  claim 51 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with disposable olefin comprising a polar functional group. 
     
     
         54 . The method of  claim 47 , wherein the cross-metathesis of the first and/or the second complementary metathesisable groups is conducted under microwave radiation conditions. 
     
     
         55 . The method of  claim 47 , wherein the cross-metathesis is performed using a cross-metathesis catalyst, and the cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst. 
     
     
         56 . The method of  claim 55 , wherein the cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst which is an alcohol. 
     
     
         57 . The method of  claim 55 , wherein the cross-metathesis is performed in a solvent combination containing about 1-30% of the coordinating solvent by volume, with respect to the total solvent combination. 
     
     
         58 . The method of  claim 47 , wherein the loading of peptide on the solid support is at least 0.2 mmol/g. 
     
     
         59 . The method of  claim 24 , further comprising:
 providing a third pair of complementary metathesisable groups in the first peptide, or one in the first peptide and one in a second or in a third peptide to be coupled to the first peptide through an intermolecular bridge;   unblocking the third pair of complementary metathesisable groups, if the metathesisable groups are blocked; and   subjecting the third pairs of complementary metathesisable groups to cross metathesis.   
     
     
         60 . 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.   
     
     
         61 . The method of  claim 60 , wherein one or both of the cross-metathesis steps is followed by a hydrogenation to form a saturated dicarba bridge between the amino acids that bore the complementary metathesisable groups. 
     
     
         62 . The method of  claim 60 , wherein the amino acids that bear the first pair of complementary metathesisable groups are selected from allyl glycine and crotyl glycine, or a combination thereof. 
     
     
         63 . The method of  claim 60 , wherein the amino acids bearing the blocked complementary metathesisable groups of the second pair of complementary metathesisable groups are prenyl glycine or protected prenyl glycine, and the reaction to unblock the blocked metathesisable groups of the second pair of complementary metathesisable groups comprises cross-metathesis with a disposable olefin. 
     
     
         64 . The method of  claim 63 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with a mono-substituted ethylene or a 1,2-disibstituted ethylene. 
     
     
         65 . The method of  claim 63 , wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with disposable olefin comprising a polar functional group. 
     
     
         66 . The method of  claim 60 , wherein the cross-metathesis of the first and/or the second complementary metathesisable groups is conducted under microwave radiation conditions. 
     
     
         67 . The method of  claim 60 , wherein the cross-metathesis is performed using a cross-metathesis catalyst, and the cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst. 
     
     
         68 . The method of  claim 67 , wherein the cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst which is an alcohol. 
     
     
         69 . The method of  claim 67 , wherein the cross-metathesis is performed in a solvent combination containing about 1-30% of the coordinating solvent by volume, with respect to the total solvent combination. 
     
     
         70 . The method of  claim 60 , wherein the loading of peptide on the solid support is at least 0.2 mmol/g. 
     
     
         71 . The method of  claim 60 , further comprising:
 providing a third pair of complementary metathesisable groups in the first peptide, or one in the first peptide and one in a second or in a third peptide to be coupled to the first peptide through an intermolecular bridge;   unblocking the third pair of complementary metathesisable groups, if the metathesisable groups are blocked; and   subjecting the third pairs of complementary metathesisable groups to cross metathesis.   
     
     
         72 . 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).   
     
     
         73 . The organic compound comprising at least two dicarba bridges produced by the method of  claim 1 . 
     
     
         74 . The peptide comprising at least two dicarba bridges produced by the method of  claim 24 . 
     
     
         75 . The peptide comprising at least two dicarba bridges produced by the method of  claim 47 .