Automated synthesis of small molecules using chiral, non-racemic boronates

Patent metadata

Field	Value
Publication number	US-9388131-B2
Application number	US-201514692088-A
Country	US
Kind code	B2
Filing date	Apr 21, 2015
Priority date	Apr 27, 2011
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

Provided are methods for making and using chiral, non-racemic protected organoboronic acids, including pinene-derived iminodiacetic acid (PIDA) boronates, to direct and enable stereoselective synthesis of organic molecules. Also provided are methods for purifying PIDA boronates from solution. Also provided are methods for deprotection of boronic acids from their PIDA ligands. The purification and deprotection methods may be used in conjunction with methods for coupling or otherwise reacting boronic acids. Iterative cycles of deprotection, coupling, and purification can be performed to synthesize chiral, non-racemic compounds. The methods are suitable for use in an automated chemical synthesis process. Also provided is an automated small molecule synthesizer apparatus for performing automated stereoselective synthesis of chiral, non-racemic small molecules using iterative cycles of deprotection, coupling, and purification.

First claim

We claim:

1. A compound of formula (II):

wherein:
B is a boron atom having sp 3 hybridization;
the carbon atom marked “*” is a chiral carbon atom of at least 90% enantiomeric excess;
R 10 is selected from the group consisting of

R 11 and each instance of R 12 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, (C1-C10)alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl, alkoxyl, acyl, acyloxy, aryloxy, amino, and trialkylsilyloxy; or R 11 and any one instance of R 12 , or any two instances of R 12 , taken together, form a 3-10-membered ring;
X is halogen;
each instance of Z is independently selected from the group consisting of CH and N, provided that no more than two instances of Z are N;
X′ is selected from the group consisting of CR 5 R 6 , O, S, and NR 7 ;
R 1 and R 2 are both hydrogen or identically selected (C1-C3)alkyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, (C1-C10)alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl, alkoxyl, acyl, acyloxy, aryloxy, amino, and trialkylsilyloxy;
R 7 and R 30 are independently selected from the group consisting of hydrogen and (C1-C3)alkyl;
n is 0, 1, or 2;
p is 0, 1, or 2; and
q is 1 or 2.

2. The compound of claim 1 , wherein the compound of formula (II) is

3. The compound of claim 1 , wherein n is 0.

4. The compound of claim 2 , wherein p is 0.

5. The compound of claim 1 , wherein R 10 is

n is 0, p is 0, each instance of R 12 is hydrogen, and R 11 is selected from the group consisting of aryl and methyl.

6. The compound of claim 1 , wherein R 10 is

n is 0, X′ is CH 2 , and R 11 is methyl.

7. The compound claim 1 , wherein R 10 is

8. The compound of claim 1 , wherein R 10 is

9. The compound of claim 1 , wherein R* is a chiral group of at least 95% enantiomeric excess.

10. A method of forming a compound of formula (II)

comprising reacting a compound represented by formula (IV)

with a compound of formula (V)
R 10 —B(OH) 2   (V),

wherein:
B in formula (II) is a boron atom having sp 3 hybridization;
the carbon atom marked “*” is a chiral carbon atom of at least 90% enantiomeric excess;
R 10 is selected from the group consisting of

R 11 and each instance of R 12 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, (C1-C10)alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl, alkoxyl, acyl, acyloxy, aryloxy, amino, and trialkylsilyloxy; or R 11 and any one instance of R 12 , or any two instances of R 12 , taken together, form a 3-10-membered ring;
X is halogen;
each instance of Z is independently selected from the group consisting of CH and N, provided that no more than two instances of Z are N;
X′ is selected from the group consisting of CR 5 R 6 , O, S, and NR 7 ;
R 1 and R 2 are both hydrogen or identically selected (C1-C3)alkyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, (C1-C10)alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl, alkoxyl, acyl, acyloxy, aryloxy, amino, and trialkylsilyloxy;
R 7 and R 30 are independently selected from the group consisting of hydrogen and (C1-C3)alkyl;
n is 0, 1, or 2;
p is 0, 1, or 2; and
q is 1 or 2.

11. The method of claim 10 , wherein the compound of formula (II) is

12. A method of performing a stereoselective chemical reaction, comprising:
contacting a compound of formula (II) with a reagent

wherein:
R 10 is chemically transformed in a stereoselective manner;
the carbon atom marked “*” is a chiral carbon atom of at least 90% enantiomeric excess;
B is a boron atom having sp 3 hybridization;
R 10 is selected from the group consisting of

R 11 and each instance of R 12 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, (C1-C10)alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl, alkoxyl, acyl, acyloxy, aryloxy, amino, and trialkylsilyloxy; or R 11 and any one instance of R 12 , or any two instances of R 12 , taken together, form a 3-10-membered ring;
X is halogen;
each instance of Z is independently selected from the group consisting of CH and N, provided that no more than two instances of Z are N;
X′ is selected from the group consisting of CR 5 R 6 , O, S, and NR 7 ;
R 1 and R 2 are both hydrogen or identically selected (C1-C3)alkyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, (C1-C10)alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl, alkoxyl, acyl, acyloxy, aryloxy, amino, and trialkylsilyloxy;
R 7 and R 30 are independently selected from the group consisting of hydrogen and (C1-C3)alkyl;
n is 0, 1, or 2;
p is 0, 1, or 2; and
q is 1 or 2.

13. The method of claim 12 , wherein the compound of formula (II) is

14. The method of claim 12 , wherein R 10 is

n is 0, p is 0, each instance of R 12 is hydrogen, and R 11 is selected from the group consisting of aryl and methyl.

15. The method of claim 12 , wherein R 10 is

n is 0, X′ is CH 2 , and R 11 is methyl.

16. The method of claim 12 , wherein R 10 is

17. The method of claim 12 , wherein R 10 is

18. The method of claim 12 , wherein the reagent is selected from the group consisting of oxidants, nucleophiles, bases, and electrophiles.

19. The method of claim 12 , wherein the chemical reaction is selected from

Assignees

• Univ Illinois

Inventors

• Burke Martin D
• Li Junqi
• Gillis Eric P

Classifications

• C07C2601/14

  The ring being saturated · CPC title

• C07D211/60

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D207/44 Primary

  having three double bonds between ring members or between ring members and non-ring members · CPC title

• C07D207/16

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C229/24

  having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid · CPC title