Synthesis of boronate salts and uses thereof

1. A method of making a compound of Formula (I-F), or a salt thereof, comprising the steps of:

(a) decomplexing and protecting of a compound of Formula (I):

to form a compound of Formula (I-B):

(b) protecting a compound of Formula (I-B) to form a compound of Formula (I-C):

(c) halomethylating a compound of Formula (I-C) to form a compound of Formula (I-D):

(d) aminating a compound of Formula (I-D) and reacting with a compound of formula:

to form a compound of Formula (I-E):

(e) deprotecting a compound of Formula (I-E) to form a compound of Formula (I-F):

wherein the deprotection comprises de-esterification and de-complexation;

wherein:

PG is a hydroxyl protecting group;

n is 0 or 1;

Y 1 is O or N + R 5 R 6

Y 2 is O or NR 10 ;

R 1 and R 2 are independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4 alkyl;

or R 1 and R 2 , together with the atoms to which they are attached, form ═O;

R 3 is selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4 alkyl;

or R 1 and R 3 , together with the atoms to which they are attached, form a carbocyclic ring;

or R 3 and R 5 , together with the atoms to which they are attached, form a heteroaryl ring;

or R 3 and R 4 , together with the atoms to which they are attached, form ═O;

R 4 , R 5 , R 6 , and R 10 are each independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4 alkyl;

R 9 is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

R 13 is selected from the group consisting of C 1-9 alkyl and C 1-9 alkyl-R 14 ; and

R 14 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl.

2. The method of claim 1 , wherein for the compound of Formula (I):

n is 1;

Y 1 is O or N + R 5 R 6

Y 2 is O;

R 1 and R 2 are independently H;

or R 1 and R 2 , together with the atoms to which they are attached, form ═O;

R 3 and R 4 are independently H;

or R 3 and R 4 , together with the atoms to which they are attached, form ═O;

R 5 and R 6 are each independently H; and

R 9 is optionally substituted C 1 -C 12 alkyl.

3. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

wherein M + is a cation selected from the group consisting of lithium, sodium, potassium, calcium, ammonium, triethylammonium, and aluminum.

4. The method of claim 2 , wherein the compound of Formula (I) is:

5. The method of claim 1 , wherein:

PG is a trialkylsilyl group; and/or

R 13 is C 1-9 alkyl-R 14 ; and/or

R 14 is optionally substituted heteroaryl, optionally thiophene-2-yl.

6. The method of claim 1 , wherein the compound of Formula (I-F) is

7. The method of claim 1 , wherein, in step (a), the decomplexing and protecting the compound of Formula (I) takes place concomitantly or in separate individual steps.

8. The method of claim 1 , wherein step (a) comprises reacting the compound of Formula (I) with a boronate protecting group compound of Formula (G):

to form the compound of Formula (I-B);

wherein, for the compound of Formula (G):

n is 0 or 1;

R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4 alkyl;

or R 1 and R 3 together with the atoms to which they are attached form a carbocyclic ring.

9. The method of claim 8 , wherein, in step (a), the decomplexing and protecting a compound of Formula (I) takes place concomitantly by mixing the compound of Formula (I) with a boronate protecting group compound of Formula (G).

10. The method of claim 8 , wherein the boronate-protecting group compound of Formula (G) is selected from the group consisting of pinanediol, pinacol, 1,2-diisopropylethanediol, 1,2-diphenylethanediol, (+) pinanediol, and (−)-pinanediol.

11. The method of claim 1 , wherein step (c) comprises treating the compound of Formula (I-C) with n-butyllithium and dichloromethane, lithium diisopropylamide and dibromomethane, or lithium hexamethyldisilazide and dibromomethane.

12. The method of claim 1 , wherein step (d) comprises treating the compound of Formula (I-D) with an amine nucleophile and reacting with the compound:

under amide coupling conditions to form the compound of Formula (I-E).

13. The method of claim 1 , wherein de-esterification and de-complexation of the compound of Formula (I-E) are accomplished in more than one step.

14. The method of claim 1 , wherein de-esterification and de-complexation of the compound of Formula (I-E) are accomplished in one step.

15. The method of claim 14 , wherein de-esterification and de-complexation of the compound of Formula (I-E) is accomplished by treatment with aqueous acid, dioxane and boronic acid.

16. The method of claim 1 , comprising the steps of:

(a) decomplexing and protecting a compound 10:

with pinanediol to form a compound 11:

(b) protecting a compound 11 to form a compound 12:

(c) halomethylating a compound 12 to form a compound 13:

(d) aminating a compound 13 and reacting with a compound of formula:

to form a compound 14:

(e) deprotecting a compound 14 to form a compound 15:

wherein the deprotection comprises de-esterification and de-complexation.

17. The method of claim 9 , wherein the mixing is in a biphasic solvent system and wherein the biphasic solvent system comprises water and one or more solvent selected from the group consisting of MTBE, CH 2 Cl 2 , ethyl acetate, 2-Me-THF, CPME, and diisopropyl ether.

18. The method of claim 10 , wherein the boronate-protecting group compound of Formula (G) is (+)-pinanediol or (−)-pinanediol.

19. The method of claim 12 , wherein the amine nucleophile is selected from the group consisting of lithium hexamethyldisilazide and ammonia.

20. The method of claim 15 , wherein the aqueous acid is sulfuric acid.