Highly fluorinated β-amino acids and methods of making and using same

1. A compound having the structure:

wherein R 1a and R 1b are independently H, alkyl, F, or fluoroalkyl;

wherein R 2a , R 2b , R 2a′ , and R 2b′ are independently H, alkyl, F, fluoroalkyl, aryl, or alkenyl;

wherein R 3 is OH, alkoxyl, NH 2 , alkylamino, or dialkylamino;

wherein R 4a and R 4b are independently H, alkyl, acyl, or alkyloxycarbonyl;

wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently H, alkyl, F, or fluoroalkyl; and

wherein C0, C1, C2, and C2′ are independently chiral or achiral.

2. The compound of claim 1 , wherein R 11 =R 12 =R 13 .

3. The compound of claim 1 , wherein R 21 =R 22 =R 23 .

4. The compound of claim 1 , wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are fluoroalkyl.

5. The compound of claim 1 , wherein R 1a , R 1b , R 2a , R 2b , R 2a′ , and R 2b′ are H; wherein C1, C2, and C2′ are achiral; and wherein the compound has the structure:

6. The compound of claim 1 , wherein R 11 =R 12 =R 13 =R 21 =R 22 =R 23 and wherein C0 is achiral.

7. The compound of claim 1 , wherein R 11 =R 12 =R 13 ≠R 21 =R 22 =R 23 and wherein C0 is chiral.

8. The compound of claim 5 , wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are CF 3 ;

wherein R 4a is H; wherein R 4b is H or Fmoc; and wherein the compound has the structure:

9. A process for making a fluorinated β-amino acid comprising the steps of:

a) providing a diol having the structure:

wherein R 1a and R 1b are independently H, alkyl, F, or fluoroalkyl;

wherein R 2a , R 2b , R 2a′ , R 2b′ , R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently H, alkyl, F, fluoroalkyl, aryl, or alkenyl;

wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently F or fluoroalkyl; and

wherein C0, C1, C2, and C2′ are independently chiral or achiral;

b) treating the diol with a thionyl halide with oxidative workup;

c) reacting the product of step (b) with an azide salt to yield an azido group;

d) oxidizing the product of step (c) to yield a carboxyl group; and

e) reducing the azido group to yield an amino group.

10. The process of claim 9 , wherein R 1a , R 2a , R 2b , R 2a′ , and R 2b′ are H; wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are CF 3 ; and wherein the compound has the structure:

11. The process of claim 9 , wherein the product of step (b) has the structure:

12. The process of claim 9 , wherein the providing step comprises the steps of:

a) providing a tetra-ol; and

b) protecting two hydroxyl groups of the tetra-ol.

13. The process of claim 12 , wherein the protecting step is reaction with a carbonyl compound to form a cyclic ketal or cyclic acetal.

14. The product produced by a process for making a fluorinated β-amino acid comprising the steps of:

a) providing a diol having the structure:

wherein R 1a and R 1b are independently H, alkyl, F, or fluoroalkyl; wherein R 2a , R 2b , R 2a′ , R 2b′ , R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently H, alkyl, F, fluoroalkyl, aryl, or alkenyl;

wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently F or fluoroalkyl; and

wherein C0, C1, C2, and C2′ are independently chiral or achiral;

b) treating the diol with a thionyl halide with oxidative workup;

c) reacting the product of step (b) with an azide salt to yield an azido group;

d) oxidizing the product of step (c) to yield a carboxyl group; and

e) reducing the azido group to yield an amino group.

15. A peptide comprising at least one residue of a compound having the structure:

wherein R 1a and R 1b are independently H, alkyl, F, or fluoroalkyl;

wherein R 2a , R 2b , R 2a′ , and R 2b′ are independently H, alkyl, F, fluoroalkyl, aryl, or alkenyl;

wherein R 3 is OH, alkoxyl, NH 2 , alkylamino, or dialkylamino;

wherein R 4a and R 4b are independently H, alkyl, acyl, or alkyloxycarbonyl;

wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently H, alkyl, F, or fluoroalkyl; and

wherein C0, C1, C2, and C2′ are independently chiral or achiral, or

at least one residue of the product of a process for making a fluorinated β-amino acid comprising the steps of:

a) providing a diol having the structure:

wherein R 1a and R 1b are independently H, alkyl, F, or fluoroalkyl; wherein R 2a , R 2b , R 2a′ , R 2b′ , R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently H, alkyl, F, fluoroalkyl, aryl, or alkenyl;

wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently F or fluoroalkyl; and

wherein C0, C1, C2, and C2′ are independently chiral or achiral;

b) treating the diol with a thionyl halide with oxidative workup;

c) reacting the product of step (b) with an azide salt to yield an azido group;

d) oxidizing the product of step (c) to yield a carboxyl group; and

e) reducing the azido group to yield an amino group.

16. The peptide of claim 15 , having the structure:

Z-βFa-Cys-M-D-Trp-Lys-A-Cys-A-X,

wherein βFa comprises a residue of a compound having the structure:

wherein R 1a and R 1b are independently H, alkyl, F, or fluoroalkyl;

wherein R 2a , R 2b , R 2a′ , and R 2b′ are independently H, alkyl, F, fluoroalkyl, aryl, or alkenyl;

wherein R 3 is OH, alkoxyl, NH 2 , alkylamino, or dialkylamino;

wherein R 4a and R 4b are independently H, alkyl, acyl, or alkyloxycarbonyl;

wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently H, alkyl, F, or fluoroalkyl; and

wherein C0, C1, C2, and C2′ are independently chiral or achiral, or

a residue of the product of a process for making a fluorinated β-amino acid comprising the steps of:

a) providing a diol having the structure:

wherein R 1a and R 1b are independently H, alkyl, F, or fluoroalkyl;

wherein R 2a , R 2b , R 2a′ , R 2b′ , R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently H, alkyl, F, fluoroalkyl, aryl, or alkenyl;

wherein R 11 , R 12 , R 13 , R 21 , R 22 , and R 23 are independently F or fluoroalkyl; and

wherein C0, C1, C2, and C2′ are independently chiral or achiral;

b) treating the diol with a thionyl halide with oxidative workup;

c) reacting the product of step (b) with an azide salt to yield an azido group;

d) oxidizing the product of step (c) to yield a carboxyl group; and

e) reducing the azido group to yield an amino group;

wherein each A independently comprises a residue of threonine or a residue of 4,4,4-trifluorothreonine;

wherein M comprises Phe or Tyr or a derivatives thereof;

wherein X comprises a terminal end group selected from carboxyl, ester, amide, and alcohol; and

wherein Z comprises a terminal end group selected from amino, formyl, acetyl, and succinyl.

17. The peptide of claim 16 , wherein the cysteine residues are linked by a disulfide bond.

18. The peptide of claim 16 , having the structure:

Z-βFa-Cys-M-D-Trp-Lys-A-Cys-tfT-X,

wherein each A independently comprises a residue of threonine or a residue of 4,4,4-trifluorothreonine; and

wherein tfT comprises a residue of 4,4,4-trifluorothreonine.

19. The peptide of claim 16 , having the structure:

Z-βFa-Cys-M-D-Trp-Lys-tfT-Cys-A-X,

wherein each A independently comprises a residue of threonine or a residue of 4,4,4-trifluorothreonine; and

wherein tfT comprises a residue of 4,4,4-trifluorothreonine.

20. The peptide of claim 16 , having the structure:

Z-βFa-Cys-M-D-Trp-Lys-tfT-Cys-tfT-X,

wherein tfT comprises a residue of 4,4,4-trifluorothreonine.