Automated synthesis of small molecules using chiral, non-racemic boronates
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. A compound of formula (I):
wherein:
B is a boron atom having sp 3 hybridization;
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 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 3 and R 4 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 is selected from the group consisting of hydrogen and (C1-C3)alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2; and
p is 0, 1, or 2.
2. The compound of claim 1 , wherein R* is
3. The compound of claim 1 , wherein R* is
4. The compound of claim 1 , wherein R* is selected from the group consisting of
5. The compound of claim 1 , wherein R* is selected from the group consisting of
6. The compound of claim 1 , wherein R* is
7. The compound of claim 1 , wherein R* is
8. The compound of claim 1 , wherein R* is
9. The compound of claim 1 , wherein R* is
10. The compound of claim 1 , wherein R 5 and R 6 are independently selected from the group consisting of hydrogen and (C1-C3)alkyl.
11. The compound of claim 1 , wherein n is 0.
12. 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.
13. The compound of claim 1 , wherein R 10 is
n is 0, X′ is CH 2 , and R 11 is methyl.
14. The compound of claim 1 , wherein R 10 is
15. The compound of claim 1 , wherein R 10 is
16. A method of forming a compound of formula (I)
comprising reacting a compound represented by formula (III)
with a compound of formula (V)
R 10 —B(OH) 2 (V),
wherein:
B in formula (I) is boron having sp 3 hybridization;
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 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 3 and R 4 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 is selected from the group consisting of hydrogen and (C1-C3)alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2; and
p is 0, 1, or 2.
17. A method of performing a stereoselective chemical reaction, comprising:
contacting a compound of formula (I) with a reagent
wherein:
R 10 is chemically transformed in a stereoselective manner;
B is a boron atom having sp 3 hybridization;
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 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 3 and R 4 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 is selected from the group consisting of hydrogen and (C1-C3)alkyl;
m is 0, 1, or 2;
n is 0, 1, or 2; and
p is 0, 1, or 2.