Automated Synthesis of Small Molecules Using Chiral, Non-Racemic Boronates

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.

1 - 144 . (canceled) 
     
     
         145 . A method of deprotecting a pinene-derived iminodiacetic acid (PIDA) boronate, comprising:
 contacting a solution comprising the chiral, non-racemic PIDA boronate and a solvent with a solid-supported ammonium hydroxide reagent, thereby deprotecting the chiral, non-racemic PIDA boronate and forming a boronic acid and a PIDA.   
     
     
         146 . The method of  claim 145 , wherein the solvent comprises THF. 
     
     
         147 . The method of  claim 145 , wherein the solid-supported ammonium hydroxide reagent binds the PIDA. 
     
     
         148 . The method of  claim 145 , further comprising the steps of removing the solvent by filtration, leaving the boronic acid and PIDA ligand trapped inside the solid-supported ammonium hydroxide reagent; and adding additional solvent. 
     
     
         149 . The method of  claim 148 , wherein the additional solvent is THF. 
     
     
         150 . The method of  claim 145 , further comprising washing the solid-supported ammonium hydroxide reagent with an organic solution comprising an organic solvent and an acid in a quantity greater than that needed to neutralize the solid-supported ammonium hydroxide reagent, thereby eluting the boronic acid. 
     
     
         151 . The method of  claim 150 , wherein the organic solvent is THF. 
     
     
         152 . The method of  claim 151 , wherein the acid is acetic acid. 
     
     
         153 . The method of  claim 152 , further comprising treating the eluted boronic acid with base to neutralize the acetic acid. 
     
     
         154 . The method of  claim 153 , wherein the base is potassium carbonate. 
     
     
         155 . The method of  claim 145 , further comprising washing the solid-supported ammonium hydroxide reagent with a 1,4-dioxane solution comprising hydrochloric acid, thereby eluting the boronic acid. 
     
     
         156 . The method of  claim 145 , wherein the solid-supported ammonium hydroxide reagent is a strong base anion exchange resin. 
     
     
         157 . The method of  claim 145 , wherein the solid-supported ammonium hydroxide reagent is a strong base, type 1, anionic, macroreticular polymeric resin based on crosslinked styrene divinylbenzene copolymer containing quaternary ammonium groups. 
     
     
         158 - 164 . (canceled)