Process improvements in steroid chemistry
View Patent ↗Steroids containing a cyclohexene moiety are efficiently oxidized to the corresponding α,β-unsaturated ketone using copper iodide and t-butyl hydroperoxide. A steroid compound containing the α,β-unsaturated ketone structure is efficiently converted to the corresponding vicinal diol using a hydroborating reagent followed by oxidative workup, e.g., borane followed by sodium perborate. Benzoyl and substituted benzoyls are superior protecting groups for hydroxyl groups present in the compounds.
1. A method comprising:
a) providing a compound of the formula:
wherein:
each of C1, C2, C4, C11, C12, C15 and C16 is independently substituted with
i) one of: ═O, ═C(R 1 )(R 1 ), —C(R 1 )(R 1 )(C(R 1 )CR 1 )) n — and —(O(C(R 1 )(R 1 )) n O)— wherein n ranges from 1 to about 6; or
ii) two of the following, which are independently selected: —X, —R 1 and —OR 2 ;
C3 is substituted with hydrogen or -ZR 3 ;
each of C8, C9 and C14 is independently substituted with one of —X, —R 1 or —OR 2 ;
C17 is substituted with two —OR 2 groups or is a ketal;
R 1 at each occurrence is independently selected from H and C 1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R 1 groups may together form a ring with the carbon atom to which they are both bonded;
R 2 is H or a protecting group such that —OR 2 is a protected hydroxyl group, where vicinal —OR 2 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 2 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 2 at C6 and C7 represents a carbonyl or protected carbonyl group;
R 3 is benzoyl or substituted benzoyl;
X represents fluoride, chloride, bromide and iodide; and
Z is selected from O, S and NR 1 ;
b) contacting the compound with reagents comprising copper iodide and t-butyl hydroperoxide to provide a mixture; and
c) maintaining the mixture of step b) under oxidizing conditions to convert to compound to a product having a carbon skeleton and an α,β-unsaturated ketone moiety as present in formula (4)
2. The method of claim 1 wherein the reagents further comprise an amine.
3. The method of claim 2 wherein the amine is pyridine.
4. The method of claim 1 wherein C1, C2, C4, C11, C12, C15 and C16 are substituted with two hydrogens, and C8, C9 and C14 are substituted with one hydrogen.
5. The method of claim 1 wherein C3 is substituted with hydrogen and —OR 3 .
6. The method of claim 1 wherein the product has the formula
wherein Z is selected from O, S and NR 1 , R 3 is benzoyl or substituted benzoyl, and except functionality shown in the structure, each carbon is fully substituted with hydrogen.
7. The method of 6 wherein R 3 is para-nitrobenzoyl and -ZR 3 is exclusively or primarily in the β-configuration.
8. The method of claim 6 wherein R 3 is benzoyl and -ZR 3 is exclusively or primarily in the β-configuration.
9. The method of claim 1 wherein Z is O.
10. The method of claim 1 wherein Z is S.
11. The method of claim 1 wherein Z is NR 1 .
12. A method comprising
a) providing a compound of the formula:
wherein:
each of C1, C2, C4, C11, C12, C15 and C16 is independently substituted with
i) one of: ═O, ═C(R 1 )(R 1 ), —C(R 1 )(R 1 )(C(R 1 )(R 1 )) n — and —(O(C(R 1 )(R 1 )) n O)— wherein n ranges from 1 to about 6; or
ii) two of the following, which are independently selected: —X, —R 1 and —OR 2 ;
C3 is substituted with hydrogen or -ZR 3 ;
each of C8, C9 and C14 is independently substituted with one of —X, —R 1 or —OR 2 ;
C17 is substituted with two —OR 2 groups or is a ketal;
R 1 at each occurrence is independently selected from H and C 1-30 organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R 1 groups may together form a ring with the carbon atom to which they are both bonded;
R 2 is H or a protecting group such that —OR 2 is a protected hydroxyl group, where vicinal —OR 2 groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR 2 groups may together form a cyclic structure which protects a carbonyl group, with the proviso that either or both of —OR 2 at C6 and C7 represents a carbonyl or protected carbonyl group;
R 3 is benzoyl or substituted benzoyl;
X represents fluoride, chloride, bromide and iodide; and
Z is selected from O, S and NR 1 ;
b) contacting the compound with reagents comprising an oxidizing agent and an amine to provide a mixture; and
c) maintaining the mixture of step b) under oxidizing conditions to convert the compound to a product having a carbon skeleton end an α,β-unsaturated ketone moiety as present in formula (4)
13. The method of claim 12 wherein the oxidizing agent is copper iodide and t-butyl hydroperoxide.
14. The method of claim 12 wherein the amine is pyridine.
15. The method of claim 12 wherein C1, C2, C4, C11, C12, C15 and C16 are substituted with two hydrogens, and C8, C9 and C14 are substituted with one hydrogen.
16. The method of claim 12 wherein C3 is substituted with hydrogen and —OR 3 .
17. The method of claim 12 wherein the compound has the formula wherein Z is selected from O, S and NR 1 , R 3 is benzyl or substituted benzoyl and, except for functionality shown in the structure, each carbon is fully substituted with hydrogen.
18. The method of claim 17 , wherein R 3 is para -nitrobenzoyl and -Zr 3 exclusively or primarily in the β-configuration.
19. The method of claim 17 , wherein R 3 is benzoyl and -ZR 3 is exclusively or primarily in the β-configuration.
20. The method of any one of claims 17 - 19 wherein Z is O.