Chemoenzymatic methods for synthesizing moenomycin analogs

1. A method of synthesizing a compound of Formula (I):

wherein

R 1 is —C(O)NHR 8 , —CH 2 OR 9 , or —C(O)OR 9 ;

R 2 and R 3 are independently hydrogen, optionally substituted aliphatic, —OR 9 , —N(R 8 ) 2 , or —C(O)NHR 8 ;

W is —O— or —NH—;

R 4 is hydrogen, a hydroxyl protecting group, optionally substituted aliphatic, —C(O)R 10 , —C(O)NHR 8 , —C(═NR 8 )NHR 8 , or —C(O)OR 9 ;

R 5 is hydrogen, an amino protecting group, optionally substituted aliphatic, or —C(O)R 10 ;

R 6 is hydrogen, —OR 9 , or —OR CX ; wherein R CX is a carbohydrate moiety;

R 7 is —OR 9 or —N(R 8 ) 2 ;

R 8 is hydrogen, an amino protecting group, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R 9 is hydrogen, a hydroxyl protecting group, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

R 10 is optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 11 is —N(R 8 ) 2 ;

q is 0, 1, 2, 3, 4, 5, or 6;

R a and R b are independently hydrogen or a hydroxyl protecting group;

G is an optionally substituted C 1-30 aliphatic group, wherein 0 to 10 methylene units are optionally replaced with —O—, —NR x —, —S—, —C(O)—, —C(═NR x ), —S(O)—, —SO 2 —, —N═N—, —C═N—, —N—O—, an optionally substituted arylene, an optionally substituted heterocyclylene, or an optionally substituted heteroarylene; or

G is a group of Formula (a), (b), or (c):

wherein a is 3, 4, or 5;

wherein

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently hydrogen or halogen;

d is an integer between 1 and 25, inclusive; and

e is an integer of between 2 and 25, inclusive;

provided the sum of d and e is greater than 16; or

wherein

Y is —O—, —S—, —NR Y —, or an optionally substituted methylene group, wherein R Y is hydrogen, optionally substituted aliphatic, or an amino protecting group;

each instance of R c is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —SR e , —NHR e , or —N(R e ) 2 , wherein each instance of R e is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R e groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;

each instance of R d is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR f , —SR f , —NHR f , or —N(R f ) 2 , wherein each instance of R f is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R f groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;

R z is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR g , —SR g , —NHR g , or —N(R g ) 2 , wherein each instance of R g is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl or two R g groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;

each instance of n is, independently, 0, 1, 2, 3, or 4;

each instance of m is, independently, 0, 1, 2, 3, or 4; and

x is 1, 2, 3, 4, 5, or 6;

comprising:

(i) providing a compound of Formula (II):

 and

(ii) reacting the compound of Formula (II) in the presence of a galactosyltransferase enzyme (GalT) with a UDP-sugar of Formula (III):

to yield a compound of Formula (I).

2. The method of claim 1 , wherein R 10 is optionally substituted aliphatic.

3. The method of claim 2 , wherein R 10 is methyl or —CH═CH 2 .

4. The method of claim 2 , wherein R 10 is substituted with halo —N 3 , —CN, —NC, —NCO, —OCN, —NCS, —SCN, —NO, —N 2 , an amino group, a hydroxyl group, aryl, heteroaryl, or optionally substituted heterocyclyl.

5. The method of claim 1 , wherein R 10 is —CH 2 aryl or —CH 2 heteroaryl.

6. The method of claim 1 , wherein R 11 is

7. The method of claim 1 , wherein the compound of Formula (III) is UDP-GalNAz, UDP-galactosamine, or UDP-GalNAc.

8. The method of claim 1 , wherein

R 1 is —C(O)NH 2 ;

R 2 is hydrogen;

R 3 is —OH;

W is —O—;

R 4 is hydrogen;

R 5 is —C(O)CH 3 ;

R 6 is —OH;

R 7 is —OH;

R a is hydrogen; and

R b is hydrogen.

9. The method of claim 1 , wherein G is

10. The method of claim 1 , wherein R 1 is —C(O)NH 2 or —CH 2 OH.

11. The method of claim 1 , wherein R 2 is hydrogen; and R 3 is —OH; or R 3 is hydrogen; and R 2 is —OH.

12. The method of claim 1 , wherein —W—R 4 is —OH, —NHC(O)NH 2 , —OC(O)NH 2 or —NHC(═NH)NH 2 .

13. The method of claim 1 , wherein R 5 is —C(O)CH 3 .

14. The method of claim 1 , wherein R 6 is —OH or —OR CX ; wherein R CX is a carbohydrate moiety.

15. The method of claim 1 , wherein R 7 is —OH.

16. The method of claim 1 , wherein the compound of Formula (II) is one of the following:

17. The method of claim 1 , wherein the compound of Formula (I) is one of the following:

18. The method of claim 1 , wherein R 11 is —NHC(O)R 10 .

19. The method of claim 18 , wherein R 10 is optionally substituted aliphatic.

20. The method of claim 19 , wherein R 10 is substituted with —N 3 .

21. The method of claim 20 , wherein R 10 —CH 2 N 3 .