Cyclopamine analogs
The invention provides novel derivatives of cyclopamine having the following formula:
1. A process for preparing a compound of formula 136:
wherein
Y is CR 7 R 8 ;
R 1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group; R 2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 1 and R 2 taken together form ═O, ═S, ═N(OR 9 ), ═N(R 9 ), ═C(R 9 ) 2 , or ═N(N(R 9 ) 2 );
each of R 3 , R 4 , and R 5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 3 and R 4 or R 4 and R 5 taken together form a bond;
R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 9 , —C(O)R 9 , —CO 2 R 9 , —SO 2 R 9 , —C(O)N(R 9 )(R 9 ), —[C(R 9 ) 2 ] q R 9 , —[(W)—N(R 9 )C(O)] q R 9 , —[(W)—C(O)] q R 9 , —[(W)—C(O)O] q R 9 , —[(W)—OC(O)] q R 9 , —[(W)—SO 2 ] q R 9 , —[(W)—N(R 9 )SO 2 ] q R 9 , —[(W)—C(O)N(R 9 )] q R 9 , —[(W)—O] q R 9 , —[(W)—N(R 9 )] q R 9 , —[(W)—S] q R 9 , or a nitrogen protecting group;
wherein each W independently for each occurrence is a diradical;
each q is independently 1, 2, 3, 4, 5, or 6;
each of R 7 and R 8 is, independently, H, alkyl, amido, halide, or ester; and
each R 9 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;
said process comprising the step of:
contacting a compound of formula 136a with a haloalkylzinc phosphate cyclopropanating agent;
wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined above;
to form said compound of formula 136;
wherein said haloalkylzinc phosphate cyclopropanating agent is formed by combining a phosphoric acid of formula 141a or salt thereof, a dialkylzinc, and a dihaloalkylane of formula 141b:
wherein
each of X and X′ is independently chloride, bromide, or iodide;
each of R 7 and R 8 is independently H, alkyl, halide, amido, or ester; and
each of R 10 and R 11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, or heteroaralkyl.
2. The process of claim 1 , wherein R 7 and R 8 are both H.
3. The process of claim 1 , wherein R 1 is a protected hydroxyl.
4. The process of claim 1 , wherein R 6 is a nitrogen protecting group.
5. The process of claim 1 ,
wherein each of R 10 and R 11 is independently aryl.
6. The process of claim 1 , wherein R 10 and R 11 are each 2,6-dimethylphenyl.
7. A process for preparing a compound of formula 137:
wherein
Y is CR 7 R 8 ;
R 1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group; R 2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 1 and R 2 taken together form ═O, ═S, ═N(OR 9 ), ═N(R 9 ), ═C(R 9 ) 2 , or ═N(N(R 9 ) 2 );
each of R 3 , R 4 , and R 5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 3 and R 4 or R 4 and R 5 taken together form a bond;
R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 9 , —C(O)R 9 , —CO 2 R 9 , —SO 2 R 9 , —C(O)N(R 9 )(R 9 ), —[C(R 9 ) 2 ] q R 9 , —[(W)—N(R 9 )C(O)] q R 9 , —[(W)—C(O)] q R 9 , —[(W)—C(O)O] q R 9 , —[(W)—OC(O)] q R 9 , —[(W)—SO 2 ] q R 9 , —[(W)—N(R 9 )SO 2 ] q R 9 , —[(W)—C(O)N(R 9 )] q R 9 , —[(W)—O] q R 9 , —[(W)—N(R 9 )] q R 9 , —[(W)—S] q R 9 , or a nitrogen protecting group;
each W independently for each occurrence is a diradical alkylene having 1-6 carbon atoms;
each q is independently 1, 2, 3, 4, 5, or 6;
each of R 7 and R 8 is, independently, H, alkyl, amido, halide, or ester;
each R 9 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;
said process comprising the steps of:
contacting a compound of formula 137a with a haloalkylzinc phosphate cyclopropanating agent;
wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined above;
to form a compound with formula 137b
wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined above; and
contacting said compound of formula 137b with an acid to give said compound of formula 137;
wherein said haloalkylzinc phosphate cyclopropanating agent is formed by combining a phosphoric acid of formula 141a or salt thereof, a dialkylzinc, and a dihaloalkylane of formula 141b:
wherein
each of X and X′ is independently chloride, bromide, or iodide;
each of R 7 and R 8 is independently H, alkyl, halide, amido, or ester; and
each of R 10 and R 11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, or heteroaralkyl.
8. The process according to claim 7 ,
wherein
R 1 is a protected hydroxyl group;
R 2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; and
R 6 is a nitrogen protecting group.
9. The process of claim 7 , wherein R 7 and R 8 are both H.
10. The process of claim 7 , wherein said protected hydroxyl group is an ester or a carbonate.
11. The process of claim 7 , wherein said nitrogen protecting group is a carbamate.
12. The process of claim 7 , wherein said nitrogen protecting group is an amide.
13. The process of claim 7 , wherein R 2 and R 3 are H and R 4 and R 5 taken together form a bond.
14. The process of claim 7 ,
wherein each of R 10 and R 11 is independently aryl.
15. The process of claim 7 , wherein said acid is acetic acid, trifluoromethanesulfonic acid, phosphoric acid, methanesulfonic acid or HCl.
16. The process of claim 7 , wherein said acid is BF 3 , zinc chloride, zinc methanesulfonate, or a zinc salt.
17. A process for preparing a compound of formula 156:
comprising the steps of:
contacting a compound of formula 156a with a haloalkylzinc phosphate cyclopropanating agent to form a compound formula 156b; and
and combining said compound of formula 156b with an acid to give said compound of formula 156;
wherein
R 1 is an oxygen protecting group selected from the group consisting of formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, pivaloate, benzoates, alkyl carbonate, alkenyl carbonate, aryl carbonates, aralkyl carbonate, 2,2,2-trichloroethyl carbonate, alkoxymethyl ether, aralkoxymethyl ether, alkylthiomethyl ether, aralkylthio ether, arylthio ether, trialkylsilyl ether, alkylarylsilyl ether, benzyl ether, arylmethyl ether, allyl ether; and
R 2 is a nitrogen protecting group selected from the group consisted of formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phenyl acetyl, benzoyl, alkyl carbamates, aralkyl carbamates, aryl carbamates, allyl, aralkyl, triarylmethyl, alkoxymethyl, aralkoxymethyl, N-2-cyanoethyl, diarylphosphinamides, dialkylphosphinamidates, diarylphosphinamidates, and trialkylsilyl;
wherein said haloalkylzinc phosphate cyclopropanating agent is formed by combining a phosphoric acid of formula 158a or salt thereof, a dialkylzinc, and a dihaloalkylane of formula 158b:
wherein
each of X and X′ is independently chloride, bromide, or iodide;
each of R 7 and R 8 is independently H, alkyl, halide, amido, or ester; and
each of R 10 and R 11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, or heteroaralkyl.
18. The process of claim 17 ,
wherein each of R 10 and R 11 is, independently, aryl.
19. The process of claim 17 , wherein said oxygen protecting group is alkyl carbonate, aralkyl carbonate, benzoate, pivaloate, or formate.
20. The process of claim 17 , wherein said nitrogen protecting group is benzoyl, trichloroacetyl, trifluoroacetyl, formyl, alkyl carbamates, aralkyl carbamates, or aryl carbamates.
21. The process of claim 17 , wherein said oxygen protecting group is benzylcarbonate.
22. The process of claim 17 , wherein said nitrogen protecting group is benzylcarbamate.
23. The process of claim 7 , wherein R 10 and R 11 are each 2,6-dimethylphenyl.
24. The process of claim 17 , wherein R 10 and R 11 are each 2,6-dimethylphenyl.
25. A process for preparing a compound of formula 136:
wherein
Y is CR 7 R 8 ;
R 1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group; R 2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 1 and R 2 taken together form ═O, ═N(OR 9 ), ═N(R 9 ), ═C(R 9 ) 2 , or ═N(N(R 9 ) 2 );
each of R 3 , R 4 , and R 5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R 3 and R 4 or R 4 and R 5 taken together form a bond;
R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 9 , —C(O)R 9 , —CO 2 R 9 , —SO 2 R 9 , —C(O)N(R 9 )(R 9 ), —[C(R 9 ) 2 ] q R 9 , —[(W)—N(R 9 )C(O)] q R 9 , —[(W)—C(O)] q R 9 , —[(W)—C(O)O] q R 9 , —[(W)—OC(O)] q R 9 , —[(W)—SO 2 ] q R 9 , —[(W)—N(R 9 )SO 2 ] q R 9 , —[(W)—C(O)N(R 9 )] q R 9 , —[(W)—O] q R 9 , —[(W)—N(R 9 )] q R 9 , —[(W)—S] q R 9 , or a nitrogen protecting group;
wherein each W independently for each occurrence is a diradical;
each q is independently 1, 2, 3, 4, 5, or 6;
each of R 7 and R 8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; and
each R 9 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;
said process comprising the step of:
contacting a compound of formula 136a with a haloalkylzinc phosphate cyclopropanating agent;
wherein
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined above;
to form said compound of formula 136;
wherein said haloalkylzinc phosphate cyclopropanating agent is formed by combining a phosphoric acid of formula 141a or salt thereof, a dialkylzinc, and a dihaloalkylane of formula 141b:
wherein
each of X and X′ is independently chloride, bromide, or iodide;
each of R 7 and R 8 is independently H, alkyl, halide, amido, or ester; and
each of R 10 and R 11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, or heteroaralkyl.