Stereoselective c9-c10 bond formation
OwnerGlenn C. MICALIZIOinventor
Life of this patent
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Abstract
The present disclosure relates to synthetic methods for preparing a 9-alpha-substituted or a 9-beta-substituted steroid-like compound. In particular, the disclosure relates to methods for generating a steroidal C9-C10 bond and establishing stereochemistry at C9 in such compounds. The methods provide high levels of stereoselection in the C9-C10 bond forming process. Compounds synthesized by such methods can be used as nuclear hormone receptor modulators.
Claims15
A method for stereoselectively preparing a 9-alpha-substituted or a 9-beta-substituted steroid-like compound (steroid numbering), the method comprising the steps of (a) providing a protodesilylated, hydroxyl-protected substrate bearing an alkene at C9-C11 and a substituent at C9;
- and (b) performing a regio- and stereoselective cyclization reaction to form a C9-C10 bond and to set a quaternary center at C9.
A compound having a structure corresponding to Formula (INT-1.1), Formula (INT-2.1), Formula (INT-3.1), Formula (INT-4.1), Formula (INT-5.1), or Formula (INT-6.1):
- wherein m is an integer selected from the group consisting of 1, 2, and 3;
- the Ar ring is a C6-10-aryl or 5- to 10-membered heteroaryl and is optionally substituted with C1-10-alkyl, C1-10-haloalkyl, C2-10-alkenyl, C2-10-haloalkenyl, C2-10-alkynyl, C2-10-haloalkynyl, oxo, or —OPg;
- G is a substituted or unsubstituted carbon atom, a substituted or unsubstituted nitrogen atom, an oxygen atom, or a sulfur atom;
- R9 is selected from the group consisting of C1-10-alkyl, C1-10-haloalkyl, C2-10-alkenyl, C2-10-haloalkenyl, C2-10-alkynyl, C2-10-haloalkynyl, each of which is optionally interrupted by one or more of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, and —NRZC(S)—, and
- wherein Q is absent or selected from the group consisting of C1-C10-alkylene, C1-C10-haloalkylene, C2-C10-alkenylene, C2-C10-haloalkenylene, C2-C10-alkynylene, and C2-C10-haloalkynylene, each of which is optionally interrupted by one or more of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, —NRZC(S)—;
- and
- E is selected from the group consisting of C6-10-aryl, 5- to 10-membered heteroaryl, C3-8-cycloalkyl, or 3- to 8-heterocycloalkyl;
- R13 is selected from the group consisting of C1-10-alkyl, C1-10-haloalkyl, C2-10-alkenyl, C2-10-haloalkenyl, C2-10-alkynyl, C2-10-haloalkynyl, each of which is optionally interrupted by one or more of —O—, —NRZ—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)NRZ—, —NRZC(O)—, —S(O)y—, —S(O)yNRZ—, —NRZS(O)y—, —C(S)NRZ—, and —NRZC(S)—, —(CH2)mx—C6-10-aryl, and —(CH2)mx-5- to 10-membered heteroaryl, where mx is an integer selected from the group consisting of 0, 1, 2, and 3;
- each Pg is an oxygen protecting group such as methyl, tert-butyloxycarbonyl (B00), methoxymethyl (MOM), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), or tribenzylsilyl;
- wherein each RZ is independently hydrogen, C1-6-alkyl, C1-6-haloalkyl, C2-6-alkenyl, C2-6-haloalkenyl, C2-6-alkynyl, C2-6-haloalkynyl, or C3-8-cycloalkyl, and y is 0, 1, or 2;
- and
- each independently represents a single bond or a double bond, provided that the bonds between C15-C16 and C16-C17 are not both double bonds.
Dependencies are inferred from the claim text.