Processes for the preparation of hydroxylated cyclohexyl compounds

1. A process for the preparation of a compound of Formula XV(i):

wherein

A is C 1-20 alkylene;

R 3 is C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkylene-R 4 , C 2-20 alkenylene-R 4 or C 2-20 alkynylene-R 4 , wherein R 4 is C 3-10 cycloalkyl, aryl or heteroaryl, and wherein the C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkylene, C 2-20 alkenylene or C 2-20 alkynylene is optionally substituted with one or more hydroxy groups; and

R 5 , R 6 and R 7 are each independently H, C 1-6 alkyl or aryl,

the process comprising:

(a) protecting a compound of Formula II under conditions to provide a compound of Formula III:

(b) protecting the compound of Formula III under conditions to provide a compound of Formula IV:

(c) reacting the compound of Formula IV with a first reducing agent under conditions to provide a compound of Formula V:

(d) reacting the compound of Formula V with a first oxidizing agent under conditions to provide a compound of Formula VI:

(e) reacting the compound of Formula VI with an alkene-forming reagent of Formula VII(a) under conditions to provide a compound of Formula VIII(a):

wherein the alkene-forming reagent is a Wittig reagent and

represents a triphenylphosphonium moiety or the alkene-forming reagent is a Horner-Wadsworth-Emmons reagent and

represents a phosphonate moiety; and

R 2 is an acetal;

(f) reacting the compound of Formula VIII(a) with a source of singlet oxygen under conditions to provide an endoperoxide of formula IX(a):

(g) reacting the endoperoxide of Formula IX(a) with a second reducing agent under conditions to provide a compound of Formula X(a):

(h) protecting the compound of Formula X(a) under conditions to provide a compound of Formula XI(a)(i):

(i) reacting the compound of Formula XI(a)(i) with a second oxidizing agent under conditions to provide a compound of Formula I(a)(i):

(j) protecting the compound of Formula I(a)(i) under conditions to provide a compound of Formula XIII(a):

(k) hydrogenating the compound of Formula XIII(a) under conditions to provide a compound of Formula XIV(a):

(l) deprotecting the compound of Formula XIV(a) under conditions to remove PG 4 and provide a compound of Formula XII(a):

(m) reacting the compound of Formula XII(a) under conditions to convert R 2 into an aldehyde to provide a compound of Formula XVI(i):

(n) reacting the compound of Formula XVI(i) with an alkene-forming reagent of Formula XVII under conditions to provide a compound of Formula XVIII(i):

wherein

the alkene-forming reagent is a Wittig reagent and

 represents a triphenylphosphonium moiety or the alkene-forming reagent is a Horner-Wadsworth-Emmons reagent and

 represents a phosphonate moiety;

(o) deprotecting the compound of Formula XVIII(i) under conditions to provide the compound of Formula XV(i) wherein R 5 , R 6 and R 7 are all H; and

(p) optionally reacting the compound of Formula XV(i) wherein R 5 , R 6 and R 7 are all H under conditions to convert one or more of R 5 , R 6 and R 7 to C 1-6 -6alkyl or aryl,

wherein

PG 1 , PG 2 , PG 3 and PG 4 are each independently protecting groups, wherein PG 1 is a protecting group that is removed by the first reducing agent and each PG 2 is the same or different or both PG 2 are joined to form a cyclic protecting group;

and

wherein in the compounds of Formulae I(a)(i), VII(a), VIII(a), IX(a), X(a), XI(a)(i), XIII(a), XIV(a), XII(a), XVI(i), XVII, XVIII(i) and XV(i), one or more available hydrogens in A, R 2 and/or R 3 is/are optionally replaced with F and/or one or more of available atoms in A, R 2 and/or R 3 is/are optionally replaced with an isotopic label.

2. The process according to claim 1 , wherein PG 1 is methyl.

3. The process according to claim 1 , wherein both PG 2 are joined to form a cyclic protecting group.

4. The process according to claim 3 , wherein both PG 2 are joined to form —C(CH 3 ) 2 —.

5. The process according to claim 1 , wherein the first reducing agent is LiBH 4 .

6. The process according to claim 1 , wherein the conditions to provide the compound of Formula VI comprise Swern oxidation conditions.

7. The process according to claim 1 , wherein the source of singlet oxygen is provided by irradiating oxygen gas and tetraphenylporphyrin.

8. The process of claim 1 , wherein the second reducing agent is thiourea.

9. The process of claim 1 , wherein PG 3 is triisopropylsilane.

10. The process of claim 1 , wherein the second oxidizing agent is 2-iodoxybenzoic acid.

11. The process according to claim 1 , wherein the alkene-forming reagent of Formula XVII is a Wittig reagent.

12. The process according to claim 1 , wherein the compound of Formula XV(i) is a compound of Formula XV(a)(i):

wherein

m is 5, 7 or 9; and

R 5 , R 6 and R 7 are each independently H, C 1-6 alkyl or aryl.

13. The process according to claim 1 , wherein the compound of Formula XV(i) is a compound of Formula XV(b)(i):

wherein

m is 5, 7 or 9; and

R 5 , R 6 and R 7 are each independently H, C 1-6 alkyl or aryl.

14. The process of claim 12 , wherein m is 5.

15. The process of claim 12 , wherein R 5 , R 6 and R 7 are all H.

16. The process of claim 12 , wherein the compound of Formula XV(a)(i) is a compound of the following structure:

17. The process according to claim 1 , wherein the conditions to convert R 2 into an aldehyde to provide the compound of Formula XVI(i) comprise selective hydrolysis of the acetal.

18. The process according to claim 17 , wherein R 2 is —C(OMe) 2 .

19. The process according to claim 1 , wherein PG 4 is —S-phenyl.

20. The process according to claim 1 , wherein the hydrogenation conditions to provide the compound of Formula XIV(a) comprise adding Wilkinson's catalyst to a solution of the compound of Formula XIII(a) in the presence of H 2 .