Processes for preparing pharmaceutically relevant peptides

1. A process for the preparation of a compound of formula VIII or a salt thereof

the method comprising reacting a compound of formula III-A or a salt thereof with a compound of formula III-B or a salt thereof to form the compound of formula VIII or the salt thereof:

wherein

A 6 together with the carbonyl group to which it is attached forms a carboxylic acid, active ester, anhydride, or acid halide;

R 1 and R 2 are each independently

(i) hydrogen;

(ii) substituted or unsubstituted C 1 -C 6 alkyl;

(iii) substituted or unsubstituted aralkyl;

(iv) substituted or unsubstituted C 3 -C 8 cycloalkyl or cycloalkylalkyl;

(v) substituted or unsubstituted C 2 -C 6 alkenyl;

(vi) an amino protecting group;

or R 1 and R 2 together form a 3, 4, 5, 6, 7, or 8 membered substituted or unsubstituted heterocyclyl or heteroaryl group;

R 8a and R 8b are each independently

where R 10 , R 11 , R 13 , and R 14 are each independently selected from H, or a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, cyano, —C(O)-alkyl, —C(O)-aryl, —C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl group, wherein each alkyl, aryl or aralkyl group is substituted or unsubstituted; and

one R 12 is —OH and the other R 12 is selected from hydrogen, —OH, halogen, C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —NH—C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , C 1 -C 4 -perhaloalkyl, aralkyl, —O— aralkyl, —NH-aralkyl, —N(aralkyl) 2 , —N(C 1 -C 6 alkyl)(aralkyl), —C(O)-alkyl, —C(O)-aryl, or —C(O)-aralkyl, wherein each alkyl, aryl or aralkyl group is substituted or unsubstituted;

R 9 is OR′ or NR′R″; R′ at each occurrence is independently a hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group; R″ is a hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group;

R 22 , R 23 , and R 24 are each independently hydrogen or a C 1 -C 4 alkyl;

n is 1, 2, 3, 4, or 5;

m is 1, 2, 3, 4, or 5;

X 1 , X 2 and X 4 are independently at each occurrence hydrogen or an amino protecting group;

X 3 is R 2 , hydrogen or an amino protecting group;

Z 5 and Z 6 are each independently —NHX 1 , —C(N—X 4 )—NH—X 2 , —NX 1 C(N—X 4 )—NH—X 2 , —NX 1 (C 1- C 6 alkyl), —NX 1 (C 6 -C 10 aryl), —NX 1 (C 7 -C 12 aralkyl), or nitrogen-containing heterocyclyl or heteroaryl group wherein each alkyl, aryl, aralkyl, heterocyclyl, or heteroaryl group is substituted or unsubstituted.

2. The process of claim 1 , wherein the compound of formula III-A or the salt thereof is prepared by a method comprising converting the compound of formula III-C or a salt thereof to the compound of formula III-A or the salt thereof:

wherein W 2 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group.

3. The process of claim 2 , wherein W 2 is benzyl and X 3 is Boc, and converting a compound of formula IIIC comprises reductively cleaving the benzyl to H.

4. The process of claim 2 , wherein R 1 and R 22 are both H, m is 3, Z 6 is —NHC(NH)NH 2 , and R 8a is 2,6-dimethyl-4-hydroxyphenyl.

5. The process of claim 1 , wherein the compound of formula III-C or the salt thereof is prepared by a method comprising reacting a compound of formula III-D or a salt thereof with a compound of formula I-E or a salt thereof to form the compound of formula III-C or the salt thereof:

6. The process of claim 1 , wherein the compound of formula III-B or the salt thereof is prepared by a method comprising converting a compound of formula III-E or a salt thereof to the compound of formula III-B or the salt thereof:

wherein Y 2 is an amino protecting group.

7. The process of claim 6 wherein Y 2 is Cbz and converting the compound of III-E comprises reductively cleaving the Cbz to H.

8. The process of claim 6 , wherein R 9 is —NH 2 , R 23 is H, n is 4, Z 5 is —NHBoc, and R 8b is unsubstituted phenyl.

9. The process of claim 6 , wherein the compound of formula III-E or the salt thereof is prepared by a method comprising reacting a compound of formula I-B or a salt thereof with a compound of formula III-F or a salt thereof to form the compound of formula III-E or the salt thereof:

wherein A 7 together with the carbonyl group to which it is attached forms a carboxylic acid, active ester, anhydride, or acid halide.

10. The process of claim 1 , wherein the compound of formula VIII or a salt thereof is a compound of formula VIII-B or a salt thereof, wherein

R 1 is hydrogen;

X 3 is an amino protecting group susceptible to acid-mediated removal;

Z 5 and Z 6 are independently selected from —NHX 1 or —NHC(NH)—NH 2 ;

X 1 is an amino protecting group susceptible to acid-mediated removal;

m and n are independently selected from 2, 3, or 4;

R 9 is NH 2 ,

R 10 and R 14 at each occurrence are independently selected from hydrogen or C 1 -C 6 alkyl; and

one R 12 is —OH and the other R 12 is hydrogen or —OH.

11. The process of claim 10 wherein X 3 is Boc and X 1 is Boc.

12. The process of claim 10 wherein the compound of formula VIII-B or a salt thereof is reacted with an acid under anhydrous conditions to provide the deprotected tetrapeptide wherein X 3 and X 1 are both hydrogen.

13. The process of claim 12 wherein the acid is HCl.

14. The process of claim 1 wherein the salt of the compound of formula VIII or VIII-B is an aliphatic carboxylate, hydrochloride, hydrobromide, alkylsulfonate, arylsulfonate, fumarate, succinate, tartrate, oxalate, phosphate, or sulfate salt.