Moenomycin analogs, methods of synthesis, and uses thereof

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

R 1a and R 1b are, independently, H, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;

each instance of R 2 , R 4 , and R 5 is, independently, H, —OR z , —N(R z ) 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein R z is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety;

R 3 is, independently, H, —OH, —NH 2 , —SH, —OR w , —NH(R w ), —N(R w ) 2 , —SR w , —O(C═O)R w , —NH(C═O)R w , —O(C═NH)R w , —NH(C═NH)R w , —S(C═NH)R w , —NH(C═S)R w , —S(C═O)R w , —O(C═S)R w , —S(═S)R w , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein R w is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;

each instance of R 6 and R 7 is, independently, H, a hydroxyl protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, —C(═O)N(R Z ) 2 , —C(═O)OR Z , wherein R z is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety; and

each instance of R 8 is, independently, H, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, or —C(═O)R w , wherein R w is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;

[Linker] is the group:

wherein:

R c is hydrogen, halogen, optionally substituted heteroaryl, —OR q , —N(R q ) 2 , —SR q , —NO 2 , —CN, —N 3 , —N(R q )═NR q , —CHO, —C(═O)R q , —C(═S)R q , —C(═NR q )R q , —C(═O)OR q , —C(═NR q )OR q , —C(═NR q )N(R q ) 2 , —C(═O)N(R q ) 2 , —C(═S)OR q , —C(═O)SR q , —C(═S)SR q , —P(═O)(OR q ) 2 , —P(═O) 2 (OR q ), —S(═O)(OR q ), —S(═O) 2 (OR q ), —P(═O)N(R q ) 2 , —P(═O) 2 N(R q ) 2 , —C(═O)NR q S(═O) 2 R q , —S(═O)N(R q ) 2 , —S(═O) 2 N(R q ) 2 , or optionally substituted heteroaryl; wherein each instance of R q is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a protecting group;

R i is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a hydroxyl protecting group; and

R 9 is H or an optionally substituted C 1-30 aliphatic moiety, wherein 0 to 10 methylene units are optionally replaced with —O—, —NR x , —S—, —C(═O)—, —C(═NR x )—, —S(═O)—, —S(═O) 2 —, —N═N—, —C(R y )═C(R y )—, an optionally substituted arylene, or an optionally substituted heteroarylene moiety, wherein each instance of R x is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, and each instance of R y is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl,

R 10 is —C(═O)NHR 8 , —CH 2 OR 6 , or —C(═O)OR 6 ;

R 11 is —OR 6 or —NHR 8 ;

R 12 is —OR 6 or —NHR 8 ;

with the proviso that the compound is not moenomycin A; moenomycin A 1.2 ; moenomycin C 1 ; moenomycin C 3 ; moenomycin C 4 ; AC326-alpha; pholipomycin; decahydromoenomycin A; decahydromoenomycin A 1.2 ; decahydromoenomycin C 1 , decahydropholipomycin; octahydro-AC326-alpha; dihydromoenomycin A; [ 3 H] moenomycin A; [ 2 H] moenomycin A; or a moenomycin compound wherein R 9 is:

2. A compound of formula (III):

or a pharmaceutically acceptable salt thereof;

wherein:

R 3 is, independently, H, —OH, —NH 2 , —SH, —OR w , —NH(R w ), —N(R w ) 2 , —SR w , —O(C═O)R w , —NH(C═O)R w , —O(C═NH)R w , —NH(C═NH)R w , —S(C═NH)R w , —NH(C═S)R w , —S(C═O)R w , —O(C═S)R w , —S(═S)R w , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein R w is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;

each instance of R 4 and R 5 is, independently, H, —OR z , —N(R z ) 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein R z is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety;

each instance of R 6 and R 7 is, independently, H, a hydroxyl protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, —C(═O)N(R Z ) 2 , —C(═O)OR Z , wherein R z is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety; and

each instance of R 8 is, independently, H, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, or —C(═O)R w , wherein R w is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;

[Linker] is the group:

wherein:

R c is hydrogen, halogen, optionally substituted heteroaryl, —OR q , —N(R q ) 2 , —SR q , —NO 2 , —CN, —N 3 , —N(R q )═NR q , —CHO, —C(═O)R q , —C(═S)R q , —C(═NR q )R q , —C(═O)OR q , —C(═NR q )OR q , —C(═NR q )N(R q ) 2 , —C(═O)N(R q ) 2 , —C(═S)OR q , —C(═O)SR q , —C(═S)SR q , —P(═O)(OR q ) 2 , —P(═O) 2 (OR q ), —S(═O)(OR q ), —S(═O) 2 (OR q ), —P(═O)N(R q ) 2 , —P(═O) 2 N(R q ) 2 , —C(═O)NR q S(═O) 2 R q , —S(═O)N(R q ) 2 , —S(═O) 2 N(R q ) 2 , or optionally substituted heteroaryl; wherein each instance of R q is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a protecting group;

R i is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a hydroxyl protecting group; and

R 9 is H,

 unsubstituted or saturated hydrocarbon chain, unsubstituted or unsaturated hydrocarbon chain, substituted or unsaturated hydrocarbon chain, an optionally substituted aryl, or an optionally substituted heteroaryl moiety,

wherein

each instance of s and t is independently 0, 1, 2, 3, 4, or 5;

each instance of R x is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, and

each instance of R y is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl;

R 10 is C(O)NHR 8 , —CH 2 OR 6 , or —C(═O)OR 6 ; and

R 11 is —OR 6 or —NHR 8 .

3. The compound according to claim 1 , wherein R 1a and R 1b are, independently, H or the group:

4. The compound according to claim 1 , wherein R 2 is —CH 3 or —CH 2 OH.

5. The compound according to claim 1 , wherein R 3 is —OH or —OR w .

6. The compound according to claim 1 , wherein R 3 is OR w , wherein R w is a carbohydrate moiety.

7. The compound according to claim 1 , wherein R 4 and R 5 are, independently, H, —CH 3 , —N(R z ) 2 , or —OR z .

8. The compound according to claim 1 , wherein each instance of R 6 is, independently, H or —C(═O)CH 3 .

9. The compound according to claim 1 , wherein R 7 is H, —C(═O)CH 3 , or —C(═O)NH 2 .

10. The compound according to claim 1 , wherein R 8 is H or —C(═O)CH 3 .

11. The compound according to claim 1 , wherein R c is —C(═O)H, —C(═O)OH, or —C(═O)NH 2 .

12. The compound according to claim 1 , wherein R i is H or a hydroxyl protecting group.

13. The compound according to claim 1 , wherein R 9 is an optionally substituted, optionally unsaturated, C 10-20 hydrocarbon chain, wherein 0 to 8 methylene units are optionally replaced with —O—, —NR x —, —S—, —C(═O)—, —C(═NR x )—, —S(═O)—, —S(═O) 2 —, —N═N—, —C(R y )═C(R y ), an optionally substituted arylene or an optionally substituted heteroarylene moiety.

14. The compound of claim 1 , wherein R 9 is an optionally substituted, optionally unsaturated, C 10 -C 16 aliphatic moiety.

15. The compound of claim 1 wherein R 9 is of one of the formulae:

16. The compound of claim 1 , wherein R 9 is a fluorinated, C 8 -C 16 alkyl moiety.

17. The compound of claim 1 , wherein R 9 is of one of the formulae:

18. The compound of claim 1 , wherein R 9 is of one of the formulae:

19. The compound of claim 1 , wherein R 9 is of the formula:

wherein each occurrence of R e is independently hydrogen or an optionally substituted aliphatic moiety.

20. The compound of claim 1 , wherein [Linker] is of formula:

21. The compound of claim 1 , wherein R 10 is —C(═O)NHR 8 .

22. The compound of claim 1 , wherein R 10 is —C(═O)NH 2 .

23. The compound of claim 1 , wherein R 11 is —OR 6 .

24. The compound of claim 1 , wherein R 11 is —OH.

25. The compound of claim 1 , wherein R 12 is —OR 6 .

26. The compound of claim 1 , wherein R 12 is —OH.

27. A pharmaceutical composition comprising a compound of claim 1 .

28. A compound of formula (IV):

or a pharmaceutically acceptable salt thereof;

wherein:

R 3 is, independently, H, —OH, —NH 2 , —SH, —OR w , —NH(R w ), —N(R w ) 2 , —SR w , —O(C═O)R w , —NH(C═O)R w , —O(C═NH)R w , —NH(C═NH)R w , —S(C═NH)R w , —NH(C═S)R w , —S(C═O)R w , —O(C═S)R w , —S(═S)R w , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein R w is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;

each instance of R 4 and R 5 is, independently, H, —OR z , —N(R z ) 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein R z is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety;

each instance of R 6 and R 7 is, independently, H, a hydroxyl protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, —C(═O)N(R Z ) 2 , —C(═O)OR Z , wherein R z is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety; and

each instance of R 8 is, independently, H, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, or —C(═O)R w , wherein R w is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;

[Linker] is the group:

wherein:

R c is hydrogen, halogen, optionally substituted heteroaryl, —OR q , —N(R q ) 2 , —SR q , —NO 2 , —CN, —N 3 , —N(R q )═NR q , —CHO, —C(═O)R q , —C(═S)R q , —C(═NR q )R q , —C(═O)OR q , —C(═NR q )OR q , —C(═NR q )N(R q ) 2 , —C(═O)N(R q ) 2 , —C(═S)OR q , —C(═O)SR q , —C(═S)SR q , —P(═O)(OR q ) 2 , —P(═O) 2 (OR q ), —S(═O)(OR q ), —S(═O) 2 (OR q ), —P(═O)N(R q ) 2 , —P(═O) 2 N(R q ) 2 , —C(═O)NR q S(═O) 2 R q , —S(═O)N(R q ) 2 , —S(═O) 2 N(R q ) 2 , or optionally substituted heteroaryl; wherein each instance of R q is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a protecting group;

R i is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a hydroxyl protecting group; and

R 9 is H, an optionally substituted C 1-30 aliphatic moiety, wherein 0 to 10 methylene units are optionally replaced with —O—, —NR x —, —S—, —C(═O)—, —C(═NR x )—, —S(═O)—, —S(═O) 2 —, —N═N—, —C(R y )═C(R y )—, an optionally substituted arylene, or an optionally substituted heteroarylene moiety, wherein each instance of R x is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, and each instance of R y is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl;

R 10 is —C(O)NHR 8 , —CH 2 OR 6 , or —C(═O)OR 6 ; and

R 11 is —OR 6 or —NHR 8 .