Synthesis of boronate ester derivatives and uses thereof

A compound having the structure of Formula (II):

• or a salt thereof, wherein:
• X is a halogen;
• m is an integer between 2 and 6;
• each of R1a and R1b is independently selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or
• R1a and R1b together with intervening atoms optionally form a 5-7 membered boron ester ring;
• and
• R2 is selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

A method of making a compound of Formula (B), comprising the steps of:

• reducing the ketone group of a compound of Formula (A):
• to form a compound of Formula (B):
• wherein:
• X is Cl;
• m is 2;
• the ketone group in the compound of Formula (A) is reduced using Ru(OAc)2((R)-SegPhos) and methanol;
• and
• the compound of Formula (B) is produced in an enantiomeric excess of greater than 99%.

A method of making a compound of Formula (B), comprising the steps of:

• reducing the ketone group of a compound of Formula (A):
• to form a compound of Formula (B):
• wherein:
• X is Cl;
• m is 2;
• and
• the ketone group in the compound of Formula (A) is reduced with an alcohol dehydrogenase system, wherein
• the alcohol dehydrogenase system comprises a reduced nicotinamide adenine dinucleotide (NADH), a reduced nicotinamide adenine dinucleotide phosphate (NADPH), and an alcohol,
• the alcohol is isopropyl alcohol,
• acetone is generated as a by-product,
• the acetone is removed under vacuum, and
• the compound of Formula (B) is produced in an enantiomeric excess of greater than 99%.

A method of making a compound of Formula (C), comprising:

• reacting a boronate compound B(OR4a)(OR4b)(OR4c) with a compound of Formula (B-1):
• to form the compound of Formula (C):
• wherein:
• X is a halogen;
• m is an integer between 2 and 6;
• R2 is selected from the group consisting of, an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R4a and R4b are independently selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or
• R4a and R4b together with intervening atoms optionally form a 5-8 membered boron ester ring;
• and
• R4c is selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

A method of making a compound of Formula (D), comprising:

• reacting magnesium with a compound of Formula (C):
• to form a first reaction intermediate;
• and
• hydrolyzing the first reaction intermediate to form the compound of Formula (D):
• wherein:
• X is a halogen;
• m is an integer between 2 and 6;
• R2 is selected from the group consisting of, an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
• and
• each of R4a and R4b is independently selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or
• R4a and R4b together with intervening atoms optionally form a 5-8 membered boron ester ring.

A method of making a compound of Formula (E), comprising

• reducing the ketone group of a keto-ester compound of Formula (A-1):
• to form a compound of Formula (B-1):
• reacting a boronate compound B(OR4a)(OR4b)(OR4c) with the compound of Formula (B-1) to form a compound of Formula (C):
• reacting magnesium with the compound of Formula (C) to form a first reaction intermediate;
• hydrolyzing the first reaction intermediate to form a compound of Formula (D):
• and
• reacting the compound of Formula (D) with a complexing agent of Formula (CL):
• to form the compound of Formula (E):
• wherein:
• X is a halogen;
• m is an integer between 2 and 6;
• n is an integer between 0 and 6;
• Y1 is O or N+R9R10;
• Y2 is O or NR11;
• R2 is selected from the group consisting of, an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R4a and R4b are independently selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or
• R4a and R4b together with intervening atoms optionally form a 5-8 membered boron ester ring;
• R4c is selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
• each R5 and R6 is independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C1-4 alkyl, or R5 and R6 together with the atom to which they are attached, form ═O;
• each R7 and R8 is independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C1-4 alkyl, or R5 and R7 together with the atom to which they are attached form an aryl or heteroaryl ring;
• or R7 and R8 together with the atom to which they are attached, form ═O;
• and
• each R9, R10 and R11 is independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C1-4 alkyl.