Preparation of maytansinoid esters
Provided are efficient methods for direct coupling of a maytansinoid with a carboxylic acid to prepare a maytansinoid C-3 ester in high yield using a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base together with a coupling reagent. Also provided are compositions used in such methods.
1. A method of preparing a compound of Formula I or a salt thereof:
comprising contacting a compound of Formula I-A:
with a carboxylic acid of the formula R—COOH in the presence of a coupling reagent, a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base to form the compound of Formula I, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, — and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein the alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclic is optionally substituted with one to three R 10 , or is
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —C(O)—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —;
substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
each R 10 is independently selected from the group consisting of —NR 11 Pr, —NR 11 COCH 2 Br, —COOR 12 , —CONR 11 R 11 , —NR 11 COR 13 ,
—S—S—R 13 , —Si(R 13 ) 3 , alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic;
each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
Pr is an amino protecting group;
R 12 is C 1 -C 6 alkyl, or benzyl; and
each R 13 is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclic.
2. The method of claim 1 , wherein the compound of Formula I is the isomer
and
the compound of Formula I-A is the isomer
3. The method of claim 1 , wherein the compound of formula I is:
and the compound of formula I-A is:
wherein X is hydrogen or Cl, Y is hydrogen or methyl, and R is as defined in claim 1 .
4. The method of claim 3 , wherein the compound of formula I is the isomer:
and the compound of formula I-A is the isomer:
wherein X is hydrogen or Cl, Y is hydrogen or methyl, and R is as defined in claim 1 .
5. The method of claim 1 , wherein the compound of formula I is:
and the compound of formula I-A is:
6. A method of preparing a compound of Formula II, or a salt thereof:
comprising contacting a compound of Formula II-A:
with a carboxylic acid of the formula R—COOH in the presence of a coupling reagent, a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base to form the compound of Formula II, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R is selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein the alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclic is optionally substituted with one to three R 10 , or is
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —C(O)—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —;
wherein substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
each R 10 is independently selected from the group consisting of —NR 11 Pr, —NR 11 COCH 2 Br, —COOR 12 , —CONR 11 R 11 , —NR 11 COR 13 ,
—S—S—R 13 , —Si(R 13 ) 3 , alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic;
each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
Pr is an amino protecting group;
R 12 is C 1 -C 6 alkyl, or benzyl; and
each R 13 is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclic.
7. The method of claim 6 , wherein the compound of Formula II is
and
the compound of Formula II-A is
8. The method of claim 1 , wherein R—COOH is
wherein
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
R 13 is C 1 -C 6 alkyl or heteroaryl;
R 15 is C 1 -C 6 alkyl, or aryl;
n is 1 or 2; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —C(O)—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; wherein substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr.
9. The method of claim 1 , wherein R—COOH is CH 3 COOH, (CH 3 ) 2 CHCOOH, (CH 3 ) 3 Si(CH 2 ) 2 OC(═O)(CH 2 ) 4 COOH,
10. The method of claim 1 , wherein R—COOH is an amino acid or amino acid derivative wherein the amino group is protected by a Pr group.
11. The method of claim 1 , wherein R—COOH is N-methyl-L-alanine, L-cysteine or L-methionine, wherein the amino group is protected by a Pr group.
12. A method of preparing a compound of Formula III, or a salt thereof:
comprising contacting a compound of Formula III-A:
with a carboxylic acid of Formula III-B
in the presence of a coupling reagent, a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base to form the compound of Formula III, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —C(O)—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; wherein substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr.
13. The method of claim 12 , wherein the compound of Formula III is the isomer:
and the carboxylic acid of Formula III-B is the isomer IV-B:
14. The method of claim 12 , wherein the compound of Formula III is the isomer:
the compound of formula III-A is the isomer:
and the carboxylic acid of Formula III-B is the isomer IV-B:
15. The method of claim 12 , wherein the compound of Formula III is a compound of Formula V, or a salt thereof:
the compound of Formula III-A is a compound of Formula V-A:
and the carboxylic acid is of Formula IV-B
16. The method of claim 15 , wherein the compound of Formula V is the isomer:
and
the compound of Formula V-A is the isomer:
17. The method of claim 12 , wherein the compound of Formula III is a compound of Formula VII, or a salt thereof:
the compound of Formula III-A is a compound of Formula VII-A:
and
the carboxylic acid is of Formula VII-B
18. The method of claim 17 , wherein the compound of Formula VII is the isomer:
and
the compound of formula VII-A is the isomer:
19. The method for preparing a compound of Formula IV, or a salt thereof:
comprising contacting a compound of Formula IV-A:
with a carboxylic acid of the formula IV-B
in the presence of a coupling reagent, a rare earth metal-based or trifluoromethanesulfonate-based Lewis acid catalyst and a base to form the compound of Formula IV, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —C(O)—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; wherein substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , —NR 11 Pr.
20. The method of claim 19 , wherein the compound of Formula IV is the isomer:
the compound of formula IV-A is the isomer:
and the carboxylic acid of the formula III-B is the isomer IV-B:
21. The method of claim 1 , wherein X is halo.
22. The method of claim 1 , wherein Y is C 1 -C 6 alkyl.
23. The method of claim 1 , wherein R 1 is hydrogen and R 2 is hydrogen or methyl.
24. The method of claim 1 , wherein R 3 is methyl.
25. The method of claim 1 , wherein R 4 is —OH.
26. The method of claim 1 , wherein L is C 1 -C 20 alkylene.
27. The method of claim 1 or 6 , wherein the Lewis acid catalyst is a lanthanide compound.
28. The method of claim 1 or 6 , wherein the Lewis acid catalyst is a trifluoromethanesulfonate (triflate) compound.
29. The method of claim 1 or 6 , wherein the Lewis acid catalyst is a lanthanide trifluoromethanesulfonate (lanthanide triflate or Ln(OTf) 3 ).
30. The method of claim 1 or 6 , wherein the Lewis acid catalyst is scandium triflate (Sc(OTf) 3 ).
31. The method of claim 1 or 6 , wherein the base is 4-dialkylaminopyridine.
32. The method of claim 1 or 6 , wherein the coupling reagent is dicyclohexylcarbodiimide, diisopropylcarbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl)-dicarbodiimide.
33. A method of preparing a compound of Formula X
comprising deprotection of a compound of Formula X-A:
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
Pr is Fmoc.
34. A method of preparing a compound of Formula XI, or a salt thereof:
or a salt thereof,
comprising contacting a compound of Formula X:
with a carboxylic acid of Formula III-G
in the presence of a coupling reagent or directly with its active ester to form the compound of Formula XI, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
R is hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl.
35. A method of preparing a compound of Formula XII:
or a salt thereof,
comprising contacting a compound of Formula X:
with a carboxylic acid of Formula III-H
in the presence of a coupling reagent or directly with its active ester to form the compound of Formula XII, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 10 —, —C(═O)NR 10 —, —NR 10 C(═O)—, —SO 2 NR 10 —, or —NR 10 SO 2 —;
substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr;
FG is independently selected from the group consisting of —NR 11 Pr, —NR 11 COCH 2 Br, —COOR 12 , —CONR 11 R 11 , —NR 11 COR 13 ,
—S—S—R 13 , —Si(R 13 ) 3 , alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic;
each R 10 or R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
Pr is an amino protecting group;
R 12 is C 1 -C 6 alkyl, or benzyl; and
each R 13 is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclic.
36. A method of preparing a compound of Formula Ma, or a salt thereof:
comprising contacting a compound of Formula X:
with a carboxylic acid of Formula III-C
in the presence of a coupling reagent or directly with its active ester to form the compound of Formula III, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —C(O)—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; wherein substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr.
37. The method of claim 36 , wherein the compound of Formula III is:
the compound of Formula X is:
and
the carboxylic acid of Formula III-C is:
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —C(O)—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; wherein substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr.
38. The method of claim 36 , wherein the compound of Formula III is:
the compound of Formula X is:
and
the carboxylic acid of Formula III-C is:
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
m is an integer of 1 to 20.
39. The method of claim 36 , wherein the compound of Formula III is:
the compound of Formula X is:
and
the carboxylic acid of Formula III-C is:
40. A method of preparing a compound of Formula XIV:
or a salt thereof,
comprising contacting a compound of Formula X:
with a sulfonyl chloride of Formula XIV-A
in the presence of a base to form the compound of Formula XIV, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 10 —, —C(═O)NR 10 —, —NR 10 C(═O)—, —SO 2 NR 10 —, or —NR 10 SO 2 —;
substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr;
FG is independently selected from the group consisting of —NR 11 Pr, —NR 11 COCH 2 Br, —COOR 12 , —CONR 11 R 11 , —NR 11 COR 13 ,
—S—S—R 13 , —Si(R 13 ) 3 , alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic;
each R 10 or R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
Pr is an amino protecting group;
R 12 is C 1 -C 6 alkyl, or benzyl; and
each R 13 is independently selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclic.
41. A method of preparing a compound of Formula XV, or a salt thereof:
comprising contacting a compound of Formula X:
with a sulfonyl chloride of Formula XV-A
in the presence of a base to form the compound of Formula XV, or a salt thereof;
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, and —OR 17 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 OR 17 ;
R 4 is —OH, —OR 17 or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 17 is a hydroxy protecting group;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —C(O)—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; wherein substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr.
42. The method of claim 41 , wherein the compound of Formula XV is:
the compound of Formula X is:
and
the sulfonyl chloride of Formula XV-A is:
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, and optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —C(O)—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; wherein substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of SH, S—C 1-4 alkyl, —CONR 11 R 11 , and —NR 11 Pr.
43. The method of claim 41 , wherein the compound of Formula XV is:
the compound of Formula X is:
and
the sulfonyl chloride of Formula XV-A is:
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl; and
m is an integer of 1 to 20.
44. The method of claim 41 , wherein the compound of Formula XV is:
the compound of Formula X is:
and
the sulfonyl chloride of Formula XV-A is: