Methods for the synthesis of dicarba bridges in organic compounds

Abstract

The present invention relates to methods for forming dicarba bridges in organic compounds. This involves the use of a pair of complementary metathesisable groups on the organic compound, and subjecting the compound to cross-metathesis under microwave radiation conditions. In an alternative, the compounds contain a turn-inducing group between the pair of cross-metathesisable groups to facilitate the cross-metathesis.

The claims defining the invention are as follows: 
     
         1 . A method for the synthesis of an organic compound with a dicarba bridge, comprising:
 providing a reactable organic compound having a pair of unblocked complementary metathesisable groups, or two or more reactable organic compounds having between them a pair of unblocked complementary metathesisable groups, and   subjecting the reactable organic compound or compounds to cross-metathesis under microwave radiation conditions to form an organic compound with an unsaturated dicarba bridge.   
     
     
         2 . The method of  claim 1 , further comprising:
 hydrogenating the unsaturated dicarba bridge.   
     
     
         3 . The method of  claim 1  or  claim 2 , 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 , in which R 5  is alkyl or an alkyl substituted by a polar functional group. 
     
     
         4 . The method of any one of  claims 1  to  3 , 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. 
     
     
         5 . The method of  claim 4 , wherein the loading of the reactable organic compound on the solid support is at least 0.2 mmol/g. 
     
     
         6 . The method of any one of  claims 4  to  5 , 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 co-ordinating solvent for the catalyst. 
     
     
         7 . The method of  claim 6 , wherein the co-ordinating solvent is an alcohol. 
     
     
         8 . The method of  claim 6  or  claim 7 , wherein the co-ordinating solvent is used in an amount of about 1-30% by volume, with respect to the total solvent combination. 
     
     
         9 . The method of any on eof  claims 1  to  8 , wherein the reactable organic compound, or the two or more reactable organic compounds, between them contain a second pair of complementary metathesisable groups which are blocked, and can be unblocked by an unblocking reaction specific to the second pair of complementary metathesisable groups, and the method further comprises unblocking the blocked second pair of complementary metathesisable groups, followed by cross-metathesis of the second pair of cross-methatesisable groups. 
     
     
         10 . The method of  claim 9 , wherein the blocked second pair of complementary metathesisable groups comprise dialkyl-blocked olefins. 
     
     
         11 . The method of  claim 9  or  claim 10 , wherein the blocked second pair of complementary metathesisable groups are unblocked by cross-methatiesis with a disposable olefin, which is 1,3-butadiene-free. 
     
     
         12 . The method of  claim 11 , wherein the disposable olefin is a 1,3-butadiene-free olefin or olefin mixture of one or more of the following: 
       
         
           
           
               
               
           
         
         wherein X and Y are each independently selected from the group consisting of H, alkyl and substituted alkyl, wherein the substituent of the substituted alkyl is selected from one or more of halo, hydroxy, alkoxy, nitrile, acid and ester. 
       
     
     
         13 . The method of any one of  claims 9  to  12 , wherein the reactable organic compound comprises a third pair of complementary methathesisable groups, which 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. 
     
     
         14 . The method of  claim 13 , 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. 
     
     
         15 . The method of  claim 14 , 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. 
     
     
         16 . The method of  claim 14 , wherein the electronic blocking group comprises ═CH—CH═CR 3 R 4 , in which 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 , in which R 5  is alkyl or an alkyl substituted by a polar functional group. 
     
     
         17 . The method of any one of  claims 1  to  16 , wherein the reactable organic compound is a peptide. 
     
     
         18 . The method of  claim 17 , wherein the organic compound with two or more dicarba bridges prepared by the method is a peptidomimetic. 
     
     
         19 . The method of  claim 17 , wherein the organic compound with two or more dicarba bridges prepared by the method is a pseudopeptide. 
     
     
         20 . The method of any one of  claims 1  to  19 , wherein the reactable organic compound comprises a peptide comprising a series of amino acids supported on a solid support, wherein two of the amino acids comprise sidechains with a first pair of complementary metathesisable groups. 
     
     
         21 . The method of  claim 20 , wherein the peptide contains at least one turn-inducing amino acid between the amino acids that comprise the first pair of complementary metathesisable groups. 
     
     
         22 . The method of  claim 21 , wherein the turn-inducing amino acids are selected from one or more of ψserine, ψthreonine and ψcysteine. 
     
     
         23 . The method of  claim 22 , further comprising cleaving the protein from the solid support and converting any ψserine, ψthreonine and ψcysteine residues present into serine, threonine and cysteine, respectively. 
     
     
         24 . A method for the synthesis of an organic compound with a dicarba bridge, comprising:
 synthesising a reactable organic compound to contain a pair of unblocked complementary metathesisable groups, and a turn-inducing group in between the pair of complementary metathesisable groups, and   subjecting the reactable organic compound to cross-metathesis to form a compound with an unsaturated dicarba bridge.   
     
     
         25 . The method of  claim 24 , further comprising hydrogenating the unsaturated dicarba bridge to form an organic compound with a saturated dicarba bridge. 
     
     
         26 . The method of any one of  claims 24  to  25 , wherein the reactable organic compound comprises a peptide comprising a series of amino acids supported on a solid support, wherein two of the amino acids comprise sidechains with a first pair of complementary metathesisable groups. 
     
     
         27 . The method of  claim 26 , wherein the peptide contains at least one turn-inducing amino acid between the amino acids that comprise the first pair of complementary metathesisable groups. 
     
     
         28 . The method of  claim 27 , wherein the turn-inducing amino acids are selected from one or more of ψserine, ψthreonine and ψcysteine. 
     
     
         29 . The method of any one of  claims 26  to  28 , 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 , in which R 5  is alkyl or an alkyl substituted by a polar functional group. 
     
     
         30 . The method of any one of  claims 26  to  29 , wherein the loading of the reactable organic compound on the solid support is at least 0.2 mmol/g. 
     
     
         31 . The method of any one of  claims 26  to  30 , 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 co-ordinating solvent for the catalyst. 
     
     
         32 . The method of  claim 31 , wherein the co-ordinating solvent is an alcohol. 
     
     
         33 . The method of  claim 31  or  claim 32 , wherein the co-ordinating solvent is used in an amount of about 1-30% by volume, with respect to the total solvent combination. 
     
     
         34 . An organic compound or a peptide containing a dicarba bridge when produced by the method of any one of  claims 1  to  33 . 
     
     
         35 . Fmoc-protected prenyl glycine. 
     
     
         36 . A method for the synthesis of Fmoc-protected prenyl glycine, the method comprising cross-metathesis of Fmoc-protected allyl glycine with 2-alkyl-2-butylene in the presence of a cross-metathesis catalyst.