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

Patent metadata

Field	Value
Publication number	US-10752577-B2
Application number	US-201916255453-A
Country	US
Kind code	B2
Filing date	Jan 23, 2019
Priority date	Apr 27, 2011
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

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 method of deprotecting a chiral, non-racemic pinene-derived iminodiacetic acid (PIDA) boronate, comprising:
contacting a solution comprising the chiral, non-racemic PIDA boronate and a solvent with an aqueous solution of NaOH, thereby deprotecting the chiral, non-racemic PIDA boronate and forming a boronic acid and free PIDA ligand.

2. The method of claim 1 , wherein the solvent comprises tetrahydrofuran (THF).

3. The method of claim 1 , further comprising the steps of adding diethyl ether, thereby generating a biphasic mixture comprising an organic phase comprising the deprotected chiral, non-racemic PIDA boronate and an aqueous phase; and isolating the organic phase comprising the boronic acid and free PIDA ligand from the aqueous phase.

4. The method of claim 3 , further comprising the step of contacting the organic phase with one or more drying agents selected from the group consisting of magnesium sulfate, diatomaceous earth, and molecular sieves, thereby drying the organic phase comprising the boronic acid and free PIDA ligand.

5. The method of claim 4 , further comprising deoxygenating the dried organic phase comprising the boronic acid and free PIDA ligand.

6. The method of claim 5 , wherein the deoxygenating comprises bubbling dry oxygen-free gas through the organic phase comprising the boronic acid and free PIDA ligand.

7. The method of claim 6 , wherein the oxygen-free gas is argon.

Assignees

• Univ Illinois

Inventors

• Burke Martin D
• Li Junqi
• Gillis Eric P

Classifications

• C07C227/32 Primary

  by stereospecific synthesis · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07C229/14 Primary

  to carbon atoms of carbon skeletons containing rings · CPC title

• C07C2602/42

  the bicyclo ring system containing seven carbon atoms · CPC title

• C07D207/44

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