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

Patent metadata

Field	Value
Publication number	US-10239824-B2
Application number	US-201615207196-A
Country	US
Kind code	B2
Filing date	Jul 11, 2016
Priority date	Apr 27, 2011
Publication date	Mar 26, 2019
Grant date	Mar 26, 2019

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 (III)

wherein:
R* is a chiral group

of at least 90% enantiomeric excess;
R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; or R 21 and R 22 , taken together, form a 5-10-membered cycloalkyl or aromatic ring, or form a 5-10-membered heterocyclic or heteroaromatic ring comprising 1-3 heteroatoms independently selected from the group consisting of O, N, and S;
R 23 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
R 1′ and R 2 are both hydrogen or identically selected (C1-C3)alkyl;
R 3 and R 4 are both hydrogen or identically selected (C1-C3)alkyl; and
m is 0, 1, or 2,
provided that the compound of formula (III) is not

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

3. The compound of claim 1 , wherein R* is

4. The compound of claim 3 , wherein R* is

5. The compound of claim 3 , wherein R* is

6. The compound of claim 1 , wherein R* is selected from the group consisting of

7. The compound of claim 6 , wherein R* is selected from the group consisting of

8. The compound of claim 6 , wherein R* is selected from the group consisting of

9. The compound of claim 1 , wherein R 21 and R 22 , taken together, form a 5-10-membered cycloalkyl or aromatic ring, or form a 5-10-membered heterocyclic or heteroaromatic ring comprising 1-3 heteroatoms independently selected from the group consisting of O, N, and S.

10. The compound of claim 9 , wherein R* is

11. The compound of claim 10 , wherein R* is

12. The compound of claim 10 , wherein R* is

13. The compound of claim 9 , wherein R* is

14. The compound of claim 13 , wherein R* is

15. The compound of claim 13 , wherein R* is

16. The compound of claim 1 , wherein m is 0.

Assignees

• Univ Illinois

Inventors

• Burke Martin D
• Li Junqi
• Gillis Eric P

Classifications

• C07C2601/14

  The ring being saturated · CPC title

• C07C227/32 Primary

  by stereospecific synthesis · 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

• C07C2601/08

  the ring being saturated · CPC title

• C07C2602/42

  the bicyclo ring system containing seven carbon atoms · CPC title