Expedient synthesis of oseltamivir and related compounds via direct olefin diazidation-diamidation reaction

1. A method of stereoselectively diazidating a cyclohexene compound of Formula (I):

wherein R 1 comprises R 1a , C(O)R 1a , C(O)OR 1a , C(O)N(R 1a ) 2 , or Si(R 1a ) 3 , wherein R 1a is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;

wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs;

R 3 is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl,

comprising contacting the compound of Formula (I) with:

a) an iron compound;

b) an azide source;

c) an activator, wherein the activator is selected from an iodine (III) compound or a peroxy compound;

d) a polydentate ligand;

to give a diazido compound of Formula (II):

wherein R 1′ is selected from R 1a′ , C(O)R 1a′ , C(O)OR 1a′ , C(O)N(R 1a′ ) 2 , Si(R 1a′ ) 3 , wherein R 1a′ is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;

wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs, or R h and R 2 together form a double bond.

2. The method according to claim 1 , wherein the polydentate ligand has the formula:

wherein m is selected from the group consisting of 0, 1, 2, and 3, and in each case R LA , R LB , R LC , and R LD are independently selected from the group consisting of R, OR, N(R) 2 , PR 3 , SiR 3 , SR, SO 2 R, SO 2 N(R) 2 , C(O)R; C(O)OR, OCOR; C(O)N(R) 2 , OC(O)N(R) 2 , N(R)C(O)N(R) 2 , F, Cl, Br, I, cyano, and nitro, wherein R is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, and C 1-8 heterocyclyl; wherein any two or more of R LA , R LB , R LC , R LD , and R may together form a ring.

3. The method according to claim 2 , wherein the polydentate ligand has the formula:

wherein each of R 7a , R 7b , R 8a , and R 8b are independently selected from the group consisting of R, OR, N(R) 2 , PR 3 , SiR 3 , SR, SO 2 R, SO 2 N(R) 2 , C(O)R; C(O)OR, OCOR; C(O)N(R) 2 , OC(O)N(R) 2 , N(R)C(O)N(R) 2 , F, Cl, Br, I, cyano, and nitro, wherein R is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 -alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, and C 1-8 heterocyclyl; wherein any two or more of R 7a , R 7b , R 8a , R 8b , R LD , and R may together form a ring.

4. The method according to claim 2 , wherein the polydentate ligand has the formula:

5. The method of claim 1 , further comprising converting the compound of Formula (II) to oseltamivir or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , further comprising converting the compound of Formula (II) to a compound of Formula (III):

wherein R 1″ is selected from R 1a″ , C(O)R 1a″ , C(O)OR 1a″ , C(O)N(R 1a″ ) 2 , Si(R 1a″ ) 3 , wherein R 1a″ is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, and heteroaryl, C 3-8 cycloalkyl.

7. The method of claim 6 , further comprising converting the compound of Formula (III) into oseltamivir or a pharmaceutically acceptable salt thereof.

8. The method of claim 6 , further comprising converting the compound of Formula (III) to a compound of Formula (IV):

wherein R 4 , R 4′ , R 5 , and R 5′ are independently selected from R z , C(O)R z , C(O)OR z , C(O)N(R z ) 2 , Si(R z ) 3 , wherein R z is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;

R 1′″ is selected from R 1a′″ , C(O)R 1a′″ , C(O)OR 1a′″ , C(O)N(R 1a′″ ) 2 , Si(R 1a′″ ) 3 , wherein R 1a′″ is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl.

9. The method of claim 8 , further comprising converting the compound of Formula (IV) into oseltamivir, or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , further comprising reducing the compound of Formula (II) into the compound of Formula (V):

wherein R 4 , R 4′ , R 5 , and R 5′ are independently selected from R z , C(O)R z , C(O)OR z , C(O)N(R z ) 2 , Si(R z ) 3 , wherein R z is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl.

11. The method of claim 10 , comprising further converting the compound of Formula (V) into oseltamivir, or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , comprising preparing the compound of Formula (I) by cycloaddition between a compound of Formula (VI):

and a compound of Formula (VII):

to give the compound of Formula (I).

13. The method of claim 10 , wherein the compound of Formula (VII) is prepared from a compound of Formula (VIII):

wherein R LG represents a leaving group.

14. A method comprising

a) conducting a cycloaddition reaction to give a cycloaddition product:

wherein R 1 comprises R 1a , C(O)R 1a , C(O)OR 1a , C(O)N(R 1a ) 2 , or Si(R 1a ) 3 , wherein R 1a is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;

wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs;

R 3 is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl; and

b) diazidating the cycloaddition product to give a compound of Formula (II):

wherein R 1′ is selected from R 1a′ , C(O)R 1a′ , C(O)OR 1a′ , C(O)N(R 1a′ ) 2 , Si(R 1a′ ) 3 , wherein R 1a′ is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, C 3-8 cycloalkyl, and C 1-8 heteroaryl;

wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs, or R h and R 2 together form a double bond.

15. The method according to claim 14 , comprising further converting the compound of Formula (II) to oseltamivir, or a pharmaceutically acceptable salt thereof.

16. A method for preparing a compound of Formula (VIII):

comprising generating in situ the compound of Formula (VII):

from a compound having the formula:

in the presence of a compound of Formula (VI):

wherein R LG is a leaving group;

wherein R 1 comprises R 1a , C(O)R 1a , C(O)OR 1a , C(O)N(R 1a ) 2 , or Si(R 1a ) 3 , wherein R 1a is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 -alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;

wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs; and

R 3 is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, C 3-8 cycloalkyl, and C 1-8 heteroaryl.

17. The method according to claim 16 , further comprising converting the compound of Formula (VIII) into oseltamivir, or a pharmaceutically acceptable salt thereof.

18. The method according to claim 17 , wherein the compound of Formula (VIII) is racemic and further comprising enzymatically resolving the compound of Formula (VIII) to obtain an enantioenriched compound of Formula (VIII-a) and an enantioenriched compound of Formula (IX):

19. The method according to claim 18 , comprising further converting the compound of Formula (VIII-a) into oseltamivir, or a pharmaceutically acceptable salt thereof.

20. A compound having the formula:

wherein R 1′ is selected from R 1a′ , C(O)R 1a′ , C(O)OR 1a′ , C(O)N(R 1a′ ) 2 , or Si(R 1a′ ) 3 , wherein R 1a′ is in each case independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, C 3-8 cycloalkyl, and C 1-8 heteroaryl;

wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs, or R h and R 2 together form a double bond; and

R 3 is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl.

21. A method, comprising enantioselectively deacylating a racemic compound of Formula (VIII):

in the presence of a lipase enzyme and aqueous solvent, to obtain an enantioenriched compound of Formula (VIII-a) and an enantioenriched compound of Formula (IX):

wherein R 1 comprises C(O)R 1a wherein R 1a is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, and C 3-8 cycloalkyl;

wherein R h is hydrogen and R 2 comprises F, Cl, Br, I, NO 2 , CN, OTs, or OMs; and

R 3 is selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, C 3-8 cycloalkyl, and C 1-8 heteroaryl.

22. The method according to claim 21 , comprising further converting the compound of Formula (VIII-a) into oseltamivir, or a pharmaceutically acceptable salt thereof.