Method of making a cross metathesis product

1. A method of making a cross metathesis product, the method comprising at least step (X) or step (Y):

(X) reacting in a cross metathesis reaction a first compound comprising a terminal olefinic group with a second compound comprising a terminal olefinic group, wherein the first and the second compound may be identical or may be different from one another; or

(Y) reacting in a ring-closing metathesis reaction two terminal olefinic groups which are comprised in a third compound;

wherein the reacting in step (X) or step (Y) is performed in the presence of a ruthenium carbene complex comprising a [Ru═C]-moiety and an internal olefin which may be a Z-olefin or an E-olefin.

2. The method of claim 1 , wherein more than 1 equivalent of said internal olefin is employed per equivalent of said first or second compound, respectively said third compound.

3. The method of claim 1 , further comprising step (Z) after step (X) or step (Y):

(Z) removing said internal olefin and/or a metathesis product which is formed from said internal olefin in step (X) or step (Y).

4. The method of claim 1 , wherein said internal olefin is a C 4-8 olefin.

5. The method of claim 1 , wherein said internal olefin is Z-2-butene or E-2-butene.

6. The method of claim 1 , wherein the first, the second or the third compound respectively comprise one or more functional groups.

7. The method of claim 1 , wherein the first and the second compound are independently from one another an alcohol, an ether, a carboxylic acid, an ester, an aldehyde, a ketone, a halogen containing compound, an amine, an amide, an imide, a sulfone, a sulfonic acid, an ester of a sulfonic acid, an internal olefin or an alkyne; or wherein the third compound is an alcohol, an ether, a carboxylic acid, an ester, an aldehyde, a ketone, a halogen containing compound, an amine, an amide, an imide, a sulfone, a sulfonic acid, an ester of a sulfonic acid, an internal olefin or an alkyne.

8. The method of claim 1 , wherein the first and the second compound used in step (X) comprise independently an amino acid moiety or a peptide moiety.

9. The method of claim 1 , wherein the third compound used in step (Y) comprises a peptide moiety.

10. The method of claim 9 , wherein the third compound used in step (C) is of formula (B)

wherein

AA is any amino acid moiety;

A is independently hydrogen, a functional group, a protecting group, an optionally substituted amino acid residue, an optionally substituted peptide residue, a solid support, or any combination thereof;

B is independently hydrogen, a functional group, a protecting group, an optionally substituted amino acid residue, an optionally substituted peptide residue, a solid support, or any combination thereof;

C is independently H, C 1 -C 4 alkyl, phenyl;

p is independently 1-4; and

s is independently 1-10.

11. The method of claim 10 , wherein the peptide formed by ring-closing metathesis of the compound of formula (B) is a stapled peptide.

12. The method of claim 1 , wherein said ruthenium carbene complex comprising a [Ru═C]-moiety is of formula I:

wherein:

M is ruthenium;

each of R 1 and L is independently a neutral ligand;

r is 1-3;

each of R 4 and R 5 is independently bonded to M through a sulfur or oxygen atom;

R 14 is a carbene;

R 4 and R 5 are taken together to form a bidentate ligand, or R 4 and R 5 are taken together with one or more of R 1 , L and R 14 to form a polydentate ligand;

two or more of R 1 , L and R 14 are optionally taken together to form a bidentate or polydentate ligand; and

each of R 1 , R 4 , R 5 , L and R 14 is independently and optionally linked to a tag or support.

13. The method of claim 12 , wherein R 4 and R 5 form a dithiolate.

14. The method of claim 12 , wherein said carbene R 14 is a benzylidene.

15. The method of claim 12 , wherein R 1 is a nitrogen-containing heterocyclic carbene and r=1.

16. The method of claim 1 , wherein the complex is of formula 4 or formula 5

wherein in formula 4 or formula 5 the substituents L and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the following meaning:

L is: a neutral ligand;

R 1 is: H;

unbranched or branched C 1-20 alkyl or unbranched or branched C 1-20 alkoxy; C 5-9 cycloalkyl or C 5-9 cycloalkoxy; optionally bearing one or more halogen atoms, respectively; or

aryl or aryloxy; optionally substituted, respectively, with one or more of unbranched or branched C 1-20 alkyl or unbranched or branched C 1-20 alkoxy, C 5-9 cycloalkyl or C 5-9 cycloalkoxy, aryl, aryloxy, unbranched or branched C 1-20 alkylcarbonyl, arylcarbonyl, unbranched or branched C 1-20 alkoxycarbonyl, aryloxycarbonyl, heteroaryl, carboxyl, cyano, nitro, amido, aminosulfonyl, N-heteroarylsulfonyl, unbranched or branched C 1-20 alkylsulfonyl, arylsulfonyl, unbranched or branched C 1-20 alkylsulfinyl, arylsulfinyl, unbranched or branched C 1-20 alkylthio, arylthio, sulfonamide, halogen or N(R y )(R z ), wherein R y and R z are independently selected from H and C 1-20 alkyl;

R 2 is: H; unbranched or branched C 1-20 alkyl; aryl; —C(O)R 12 ; —C(O)OR 12 ; —C(O)C(O)R 12 ; —C(O)C(O)OR 12 ; wherein R 12 has the meaning of C 1-20 alkyl or aryl, respectively; R 12 optionally bearing one or more halogen atoms;

R 3 is: unbranched or branched C 1-20 alkyl; aryl; or

R 13 —C(O)—CHR 14 , wherein R 13 is C 1-20 alkoxy and R 14 is H or C 1-20 alkyl; or

wherein R 13 is C 1-20 alkoxy and R 14 is C(O)—O—C 1-20 alkyl; or wherein R 13 is C 1-20 alkyl and R 14 is H; or R 13 is OH and R 14 is H or C 1-20 alkyl; or

R 15 —O—N(R 16 )—C(O)—CHR 17 , wherein R 15 , R 16 , and R 17 are independently H or C 1-20 alkyl;

R 4 is: H;

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are, independently, H; unbranched or branched C 1-20 alkyl or unbranched or branched C 1-20 alkoxy; C 5-9 cycloalkyl or C 5-9 cycloalkoxy; aryl; aryloxy; unbranched or branched C 1-20 alkylcarbonyl; arylcarbonyl; unbranched or branched C 1-20 alkoxycarbonyl; aryloxycarbonyl; heteroaryl; carboxyl; cyano; nitro; amido; aminosulfonyl; N-heteroarylsulfonyl; unbranched or branched C 1-20 alkylsulfonyl; arylsulfonyl; unbranched or branched C 1-20 alkylsulfinyl; arylsulfinyl; unbranched or branched C 1-20 alkylthio; arylthio; sulfonamide; halogen; or N(R y )(R z ), wherein R y and R z are independently selected from H and C 1-20 alkyl; or

aryl or aryloxy, respectively substituted with one or more of unbranched or branched C 1-20 alkyl or unbranched or branched C 1-20 alkoxy, C 5-9 cycloalkyl or C 5-9 cycloalkoxy, aryl, aryloxy, unbranched or branched C 1-20 alkylcarbonyl, arylcarbonyl, unbranched or branched C 1-20 alkoxycarbonyl, aryloxycarbonyl, heteroaryl, carboxyl, cyano, nitro, amido, aminosulfonyl, N-heteroarylsulfonyl, unbranched or branched C 1-20 alkylsulfonyl, arylsulfonyl, unbranched or branched C 1-20 alkylsulfinyl, arylsulfinyl, unbranched or branched C 1-20 alkylthio, arylthio, sulfonamide, halogen or N(R y )(R z ), wherein R y and R z are independently selected from H and C 1-20 alkyl.

17. The method of claim 16 , wherein in formula 4 or 5 the neutral ligand L is

P(R x ) 3 , wherein R x is independently branched or unbranched C 1-20 alkyl or C 1-20 alkoxy, C 5-9 cycloalkyl, or aryl; or

RCN, wherein R is branched or unbranched C 1-20 alkyl, C 5-9 cycloalkyl, or aryl; or

a carbene containing the moiety of formula 6

wherein R 7 and R 8 as defined in formula 6 are each independently H, unbranched or branched C 1-20 alkyl, C 5-9 cycloalkyl, or phenyl, wherein the phenyl is optionally substituted with up to three groups independently selected from unbranched or branched C 1-6 alkyl, C 1-6 alkoxy or halogen.

18. The method of claim 16 , wherein L in formula 4 or 5 is a carbene of one of formulas 6a, 6b, 6c or 6d:

wherein R 9 and R 10 are each independently H, unbranched or branched C 1-20 alkyl, or phenyl, wherein the phenyl is optionally substituted with up to three groups independently selected from unbranched or branched C 1-6 alkyl, C 1-6 alkoxy or halogen; or

R 9 and R 10 together with the carbon atoms to which they are attached are combined to form a carbocyclic 3 to 8 membered ring;

Y and Y′ are halogen.

19. The method of claim 16 , wherein R 1 is C 1-6 alkyl, optionally substituted with one or more of halogen; or phenyl, optionally substituted with one or more of unbranched or branched C 1-20 alkyl or unbranched or branched C 1-20 alkoxy, C 5-9 cycloalkyl or C 5-9 cycloalkoxy, aryl, aryloxy, unbranched or branched C 1-20 alkylcarbonyl, arylcarbonyl, unbranched or branched C 1-20 alkoxycarbonyl, aryloxycarbonyl, heteroaryl, carboxyl, cyano, nitro, amido, aminosulfonyl, N-heteroarylsulfonyl, unbranched or branched C 1-20 alkylsulfonyl, arylsulfonyl, unbranched or branched C 1-20 alkylsulfinyl, arylsulfinyl, unbranched or branched C 1-20 alkylthio, arylthio, sulfonamide, halogen or N(R y )(R z ), wherein R y and R z are independently selected from H and C 1-20 alkyl.

20. The method of claim 16 , wherein R 2 is H.

21. The method of claim 16 , wherein NR 2 —C(O)—R 1 is in para-position with respect to O.

22. The method of claim 16 , wherein R 3 is methyl or isopropyl.

23. The method of claim 16 , wherein R 5 is H.

24. The method of claim 16 , wherein R 6 , R 7 , R 8 , and R 9 in formula 4 are independently selected from H and halogen.

25. The method of claim 16 , wherein R 10 and R 11 as defined in formula 5 are independently selected from halogen and cyano.

26. The method of claim 16 , wherein L is of formula 6a or 6b, and R 7 and R 8 as defined in formula 6a and 6b are mesityl, or 2,6-diisopropylphenyl; or

wherein L is of formula

27. The method of claim 16 , wherein the complex is immobilized on a solid support.

28. The method of claim 15 , wherein R 1 as defined in claim 15 is nitrogen-containing heterocyclic carbene of structure 7

wherein the A-ring is a 4-, 5-, 6-, or 7-membered ring; and L in formula 7 is a linking group representing from one to four ring vertices selected from carbon with available valences optionally occupied by hydrogen or optionally substituted by C 1-10 alkyl and aryl, optionally substituted;

R in formula 7 represents a member selected from C 1-10 alkyl and aryl, optionally substituted;

R 1 and R 2 in formula 7 represent independently members selected from C 1-10 alkyl and aryl, optionally substituted.

29. The method of claim 28 , wherein the nitrogen-containing carbene is of formula 7a or 7b:

wherein R, R 1 , R 2 , R 3 and R 4 in formulae 7a and 7b independently represent a member selected from C 1-10 alkyl and aryl, optionally substituted.

30. The method of claim 1 , wherein the complex is selected from one of the following structures:

and EWG is an electron-withdrawing group.

31. The method of claim 1 , wherein more than 50% or 60% or 70% or 80% of the olefin formed in the metathesis reaction according to step (X) or (Y) is a Z-olefin, provided said internal olefin is a Z-olefin; or

wherein the olefin formed in the metathesis reaction according to step (X) is generated predominantly as E-olefin, provided said internal olefin is an E-olefin; or

wherein the olefin formed in the metathesis reaction according to step (Y) is generated predominantly as E-olefin, provided said internal olefin is an E-olefin, and the ring-closing metathesis reaction allows the formation of an E-olefin depending on the ring size.

32. A method of reducing activity loss of a Ru carbene complex comprising a [Ru═C]-moiety when using said complex in a metathesis reaction in which ethylene is developed, the method comprising step (V):

(V) performing said reaction in the presence of an internal olefin.

33. The method of claim 32 , wherein said internal olefin is Z-2-butene or E-2-butene.