Synthesis of boronate salts and uses thereof
Disclosed herein are boronate intermediates in the synthesis of antimicrobial compounds and the use and preparation thereof. Some embodiments relate to crystalline boronate salt derivatives and their use in the synthesis of therapeutic compounds.
1. A compound of Formula (I)
or a salt thereof, wherein:
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 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 independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4 alkyl; and
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.
2. The compound of claim 1 , wherein Y 1 is O.
3. The compound of claim 1 , wherein Y 1 is N + R 5 R 6 .
4. The compound of claim 1 , wherein Y 2 is O.
5. The compound of claim 1 , wherein R 1 and R 2 are both H.
6. The compound of claim 1 , wherein R 1 and R 2 together with the atoms to which they are attached, form ═O and wherein R 3 and R 4 together with the atoms to which they are attached, form ═O.
7. The compound of claim 1 , wherein R 3 and R 4 are both H.
8. The compound of claim 1 , wherein R 5 and R 6 are both H.
9. The compound of claim 1 , wherein R 9 is optionally substituted C 1 -C 12 alkyl.
10. The compound of claim 1 , having a structure 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.
11. A method of making a compound of Formula (I), or a salt thereof, comprising the steps of:
(a) protecting the hydroxy group of a compound of Formula (A):
to form a compound of Formula (B):
(b) reacting a compound of Formula (B) with a compound of Formula (C):
to form a compound of Formula (D):
(c) deprotecting a compound of Formula (D) to form a compound of Formula (E):
(d) reacting a compound of Formula (E) with a complexing agent of Formula (F):
to form a compound of Formula (I):
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 an aryl or 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 independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4 alkyl;
R 9 is 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, or optionally substituted heteroaryl;
R 11 is selected from the group consisting of substituted or unsubstituted variants of the following: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkynyl, C 3 -C 12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and (cycloalkyl)alkyl, and
X is selected from the group consisting of substituted or unsubstituted variants of the following: C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl; and
R 12 is selected from the group consisting of substituted or unsubstituted variants of the following: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkynyl, C 3 -C 12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and (cycloalkyl)alkyl.
12. The method of claim 11 , wherein R 1 and R 2 are both H.
13. The method of claim 11 , wherein R 1 and R 2 together with the atoms to which they are attached, form ═O and wherein R 3 and R 4 together with the atoms to which they are attached, form ═O.
14. The method of claim 11 , wherein R 3 and R 4 are both H.
15. The method of claim 11 , wherein R 5 and R 6 are both H.
16. The method of claim 11 , wherein R 9 is optionally substituted C 1 -C 12 alkyl.
17. A method of making a compound of Formula (I), or a salt thereof,
comprising the steps of:
reacting a compound of Formula (E):
with a complexing agent of Formula (F):
to form a compound of Formula (I):
wherein
n is 0 or 1,
Y 1 is O or N + R 5 R 6
Y 2 ═O or NR 10 ,
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 10 are independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C 1-4 alkyl; or
wherein independently two geminal R 1 , R 2 , R 3 , R 4 together with the atoms to which they are attached, form ═O; and
wherein R 9 is 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 or, optionally substituted heteroaryl.
18. The method of claim 17 , wherein n is 1.
19. The method of claim 17 , wherein Y 1 is N + R 5 R 6 .
20. The method of claim 17 , wherein Y 2 is NR 10 .
21. The method of claim 17 , wherein R 1 and R 2 are both H.
22. The method of claim 17 , wherein R 3 and R 4 are both H.
23. The method of claim 17 , wherein R 1 and R 2 together with the atoms to which they are attached, form ═O and wherein R 3 and R 4 together with the atoms to which they are attached, form ═O.
24. The method of claim 17 , wherein R 5 and R 6 are both H.
25. The method of claim 17 , wherein R 9 is optionally substituted C 1 -C 12 alkyl.
26. The method of claim 17 , wherein R 9 is t-butyl.