Synthesis of amino acid keto-epoxides

1 . A method for the synthesis of amino acid keto-epoxides comprising a sequence of reactions according to scheme (I)

wherein

R 1 is selected from a protecting group or a further chain of amino acids, which itself may be optionally substituted;

R 2 is selected from hydrogen and C 1-6 alkyl; or

R 1 and R 2 together are C(O)-aryl-C(O) or C(O)C 1-6 alkenylC(O), thereby forming a ring;

R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl;

A is a stereoselective reduction under reducing conditions;

B is a stereoselective epoxidation under epoxidizing conditions; and

C is an oxidation under oxidizing conditions:

2 . A method of claim 1 , wherein R 1 is a protecting group.

3 . A method of claim 2 , wherein R 1 is an electron withdrawing protecting group.

4 . A method of claim 3 , wherein R 1 is selected from t-butoxy carbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), and benzyloxy carbonyl (Cbz).

5 . A method of claim 4 , wherein R 1 is Cbz.

6 . A method of claim 4 , wherein R 2 is hydrogen.

7 . A method of claim 1 , wherein A is selected from sodium borohydride with cerium trichloride, lithium tri-tert-butoxyaluminum hydride, or L-selectride.

8 . A method of claim 7 , wherein A is sodium borohydride with cerium trichloride.

9 . A method of claim 1 , wherein B is selected from m-chloroperbenzoic acid or VO(acac) 2 with t-BuOOH.

10 . A method of claim 9 , wherein B is VO(acac) 2 with t-BuOOH.

11 . A method of claim 1 , wherein C is selected from a Swern oxidation or an oxidation wherein the oxidizing reagent(s) is Dess-Martin periodinane or tetrapropylammonium perruthenate (TPAP) with 4-methylmorpholine-N-oxide (NMO).

12 . A method of claim 11 , wherein C is a Swern oxidation.

13 . A method of claim 11 , wherein C is a oxidation with Dess-Martin periodinane.

14 . A method of claim 1 , wherein the compounds in scheme (I) have the following stereochemistry

15 . A method of claim 1 , further comprising removing the protecting group if necessary and coupling with a chain of amino acids.

16 . A method of claim 15 , wherein the chain of amino acids comprises three amino acids.

17 . A method of claim 16 , wherein the chain of amino acids has a structure of formula (VII)

is X is COOH or an activated form thereof;

R 5 , R 6 , and R 7 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether;

R 9 is a further chain of amino acids, hydrogen, C 1-6 acyl, a protecting group, aryl, or heteroaryl, where substituents include halogen, carbonyl, nitro, hydroxy, aryl, and C 1-5 alkyl.

18 . A method of claim 17 , wherein X is COOH or COCl, R 5 and R 7 are C 1-6 aralkyl, R 6 is C 1-6 alkyl, and R 9 is C 1-6 acyl.

19 . A method of claim 18 , wherein X is COOH, R 5 is 2-phenylethyl, R 6 is isobutyl, R 7 is phenylmethyl, and R 9 is acetyl.

20 . A method for the synthesis of an allyl alcohol according to scheme (II)

wherein

R 1 is selected from a protecting group or a further chain of amino acids, which itself may be optionally substituted;

R 2 is selected from hydrogen and C 1-6 alkyl; or

R 1 and R 2 together are C(O)-aryl-C(O) or C(O)C 1-6 alkenylC(O), thereby forming a ring;

R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; and

A is a stereoselective reduction under reducing conditions.

21 . A method for the synthesis of an epoxide according to scheme (III)

wherein

R 1 is selected from a protecting group or a further chain of amino acids, which itself may be optionally substituted;

R 2 is selected from hydrogen and C 1-6 alkyl; or

R 1 and R 2 together are C(O)-aryl-C(O) or C(O)C 1-6 alkenylC(O), thereby forming a ring;

R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; and

B is a stereoselective epoxidation under epoxidizing conditions.

22 . A method for the synthesis of amino acid keto-epoxides according to scheme (IV)

wherein

R 1 is selected from a protecting group or a further chain of amino acids, which itself may be optionally substituted;

R 2 is selected from hydrogen and C 1-6 alkyl; or

R 1 and R 2 together are C(O)-aryl-C(O) or C(O)C 1-6 alkenylC(O), thereby forming a ring;

R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; and

C is an oxidation under oxidizing conditions.