Cross-coupling of unactivated secondary boronic acids
Provided are methods for site- and stereo-retentive cross-couplings with unactivated secondary boronic acids, which methods are particularly useful in building block-based approach for small molecule synthesis. Also provided is a method of forming an air-stable chiral secondary boronic acid.
1. A method of forming a chiral non-racemic secondary boronic acid, comprising:
combining a chiral compound of formula (I)
wherein, independently for each occurrence, R 1 and R 2 are selected from the group consisting of substituted C 1 -C 6 alkyl and unsubstituted C 1 -C 6 alkyl; a chiral iminodiacetic acid, wherein the chiral iminodiacetic acid is not a racemic mixture; pyridinium p-toluenesulfonate (PPTS); and a polar aprotic solvent, thereby forming a mixture of chiral boronates;
resolving the mixture of chiral boronates into individual diastereomers; and
hydrolyzing an individual diastereomer,
thereby forming the chiral non-racemic secondary boronic acid.
2. The method of claim 1 , wherein the hydrolyzing is with aqueous hydroxide.
3. The method of claim 1 , wherein the chiral iminodiacetic acid has an enantiomeric excess of at least 80 percent.
4. The method of claim 1 , wherein the chiral iminodiacetic acid is benzylcyclopentyl iminodiacetic acid (BIDA).
5. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 80 percent.
6. The method of claim 1 , wherein the resolving is by crystallization.
7. The method of claim 1 , wherein the resolving is by chromatography.
8. The method of claim 1 , wherein the hydrolyzing is with aqueous NaOH.
9. The method of claim 1 , wherein the chiral iminodiacetic acid has an enantiomeric excess of at least 90 percent.
10. The method of claim 1 , wherein the chiral iminodiacetic acid has an enantiomeric excess of at least 95 percent.
11. The method of claim 1 , wherein the polar aprotic solvent is CH 3 CN.
12. The method of claim 1 , wherein the compound of formula (I) is a racemic mixture.
13. The method of claim 1 , wherein the compound of formula (I) is not a racemic mixture.
14. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 90 percent.
15. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 95 percent.
16. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 80 percent; and the chiral iminodiacetic acid has an enantiomeric excess of at least 80 percent.
17. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 90 percent; and the chiral iminodiacetic acid has an enantiomeric excess of at least 90 percent.
18. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 95 percent; and the chiral iminodiacetic acid has an enantiomeric excess of at least 95 percent.
19. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 80 percent; the chiral iminodiacetic acid has an enantiomeric excess of at least 80 percent; and the compound of formula (I) is a racemic mixture.
20. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 90 percent; the chiral iminodiacetic acid has an enantiomeric excess of at least 90 percent; and the compound of formula (I) is a racemic mixture.
21. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid has an enantiomeric excess of at least 95 percent; and the compound of formula (I) is a racemic mixture.
22. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid has an enantiomeric excess of at least 95 percent; and the chiral iminodiacetic acid is benzylcyclopentyl iminodiacetic acid (BIDA).
23. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid is benzylcyclopentyl iminodiacetic acid (BIDA); and the compound of formula (I) is a racemic mixture.
24. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid is benzylcyclopentyl iminodiacetic acid (BIDA); the compound of formula (I) is a racemic mixture; and the hydrolyzing is with aqueous hydroxide.
25. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid is benzylcyclopentyl iminodiacetic acid (BIDA); the compound of formula (I) is a racemic mixture; and the hydrolyzing is with aqueous NaOH.
26. The method of claim 1 , wherein the chiral non-racemic secondary boronic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid has an enantiomeric excess of at least 95 percent; the chiral iminodiacetic acid is benzylcyclopentyl iminodiacetic acid (BIDA); the compound of formula (I) is a racemic mixture; the hydrolyzing is with aqueous NaOH; and the polar aprotic solvent is CH 3 CN.