Methods and compounds useful for the preparation of sodium glucose co-transporter 2 inhibitors

1. A method of preparing a compound of formula I:

or a salt thereof, which comprises contacting a compound of formula II:

with a base under conditions sufficient to provide the compound of formula I, wherein:

Y is O, S, NR 4 , or C(R 4 ) 2 ;

Z 1 is O, S, SO, or SO 2 ;

each P 1 is independently a hydroxyl protecting group stable under acidic conditions;

each R 1 is independently hydrogen, halogen, cyano, OR 1A , SR 1A , or optionally substituted alkyl;

each R 1A is independently hydrogen or optionally substituted alkyl or aryl;

each R 2 is independently hydrogen, halogen, cyano, OR 2A , SR 2A , or optionally substituted alkyl;

each R 2A is independently hydrogen or optionally substituted alkyl or aryl;

R 3 is optionally substituted alkyl, aryl or heterocycle;

each R 4 is independently hydrogen or optionally substituted alkyl or aryl;

n is 1-3; and

m is 1-3.

2. The method of claim 1 , wherein the compound of formula I is of the formula:

3. The method of claim 1 , wherein the compound of formula I is of the formula:

4. The method of claim 1 , wherein the base is alkoxide, hydroxide, carbonate, or amine.

5. The method of claim 1 , wherein the compound of formula II is prepared by oxidizing a compound of formula II(a):

wherein Z 2 is S or SO.

6. The method of claim 5 , wherein the oxidation is achieved using a peroxy compound.

7. The method of claim 6 , wherein the peroxy compound is m-chlorophenylperacid, peracetic acid, oxone, or a mixture of hydrogen peroxide or hydrogen peroxide complex and acid anhydride.

8. A method of preparing a compound of formula II(b):

or a salt thereof, which comprises contacting a compound of formula II(c):

with a compound of the formula R 3 X under conditions sufficient to provide the compound of formula II(b), wherein:

X is bromine, iodine, alkanesulfoxy, or alkoxysulfoxy;

Y is O, S, NR 4 , or C(R 4 ) 2 ;

each P 1 is independently a hydroxyl protecting group stable under acidic conditions;

each R 1 is independently hydrogen, halogen, cyano, OR 4 , SR 4 , or optionally substituted alkyl;

each R 2 is independently hydrogen, halogen, cyano, OR 4 , SR 4 , or optionally substituted alkyl;

R 3 is optionally substituted alkyl, aryl or heterocycle;

each R 4 is independently hydrogen or optionally substituted alkyl;

n is 1-2; and

m is 1-2.

9. The method of claim 8 , wherein X is bromine.

10. The method of claim 8 , wherein X is iodine.

11. The method of claim 8 , wherein X is sulfoxy.

12. The method of claim 8 , wherein the compound of formula II(b) is of the formula:

13. The method of claim 8 , wherein the compound of formula II(c) is prepared by contacting a compound of formula II(d):

with a Lewis acid and thiourea under conditions sufficient to provide the compound of formula II(c).

14. The method of claim 13 , wherein the Lewis acid is trimethylsilyl trifluoromethanesulfonate.

15. A method of preparing a compound of formula II(d):

or a salt thereof, which comprises contacting a compound of formula II(e):

with a salt of P 1 X′″ under conditions sufficient for the formation of the compound of formula II(d), wherein:

X′″ is chlorine, bromine, iodine, alkylcarboxy, alkanesulfoxy, or alkoxysulfoxy;

Y is O, S, NR 4 , or C(R 4 ) 2 ;

each P 1 is independently a hydroxyl protecting group stable under acidic conditions;

each R 1 is independently hydrogen, halogen, cyano, OR 4 , SR 4 , or optionally substituted alkyl;

each R 2 is independently hydrogen, halogen, cyano, OR 4 , SR 4 , or optionally substituted alkyl;

each R 4 is independently hydrogen or optionally substituted alkyl;

n is 1-2; and

m is 1-2.

16. The method of claim 15 , wherein X′″ is chlorine or acetoxy.

17. The method of claim 15 , wherein the compound of formula II(d) is of the formula:

18. The method of claim 15 , wherein the compound of formula II(e) is prepared by contacting a compound of formula III(a):

with an acid under conditions sufficient to provide the compound of formula II(e), wherein each P 2 is independently C(O)R 6 , or both P 2 s are taken together to provide C(R 6 ) 2 , wherein each R 6 is independently alkyl, aryl, alkylaryl, or arylalkyl.

19. The method of claim 18 , wherein the compound of formula III(a) is of the formula:

20. The method of claim 18 , wherein the acid is acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, or toluenesulfonic acid.

21. The method of claim 18 , wherein the compound of formula III(a) is prepared by reducing a compound of formula III(b):

22. The method of claim 21 , wherein the compound of formula III(b) is of the formula:

23. The method of claim 21 , wherein the reduction is achieved using cerium chloride and sodium borohydride, a borane complex, enzymatic reduction, hydrogenation, or transfer hydrogenation.

24. The method of claim 21 , wherein the compound of formula III(b) is prepared by contacting a compound of formula IV:

with a compound of formula V:

under conditions sufficient to provide the compound of formula III(b), wherein: X′ is bromine or iodine; and X″ is a leaving group.

25. The method of claim 24 , wherein the conditions sufficient to provide the compound of formula III(b) comprise the use of a metalating or transmetalating agent.

26. The method of claim 25 , wherein the metalating agent is magnesium or lithium.

27. The method of claim 25 , wherein the transmetalating agent is a magnesium reagent or an organolithium reagent.

28. The method of claim 24 , wherein the compound of formula IV is of the formula:

29. The method of claim 28 , wherein the compound of formula IV is of the formula:

30. The method of claim 24 , wherein the compound of formula V is of the formula:

31. A method of preparing ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone:

which comprises contacting (3a8,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid with morpholine under conditions sufficient to provide ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone.

32. The method of claim 31 , wherein (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid is prepared by oxidizing (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol under conditions sufficient to provide (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid.

33. The method of claim 32 , wherein the (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol is prepared by cyclizing L-(−)-xylose in the presence of acetone under conditions sufficient to provide (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol.

34. A crystalline compound of the formula:

35. A compound of the formula:

or a salt thereof.

36. A compound of the formula:

or a salt thereof.

37. A compound of the formula:

or a salt thereof.

38. A compound of the formula:

or a salt thereof.

39. A compound of the formula:

or a salt thereof.

40. A compound of the formula:

41. A compound of the formula:

42. A compound of the formula:

or a salt thereof.