C19 scaffolds and steroids and methods of use and manufacture thereof

A method for preparing a chiral tetracyclic compound of Formula (ii), the method comprising a step of:

• (a) converting an unsaturated hydrindane of Formula (i) to the compound of Formula (ii), wherein step (a) is optionally carried out in the presence of a chiral catalyst or reagent;
• and
• optionally, (b) shifting a substituent of the compound of Formula (ii) from C9 to C10, wherein step (a) and optional step (b) are represented by the following scheme:
• wherein n is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
• each RA is independently selected from the group consisting of hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, halogen, —ORAX, SRAY, —S(O)2NRZ1RZ2, —S(O)2RZ1, —S(O)RZ1, —NRZ1RZ2, —N(RZ1)C(O)RZ2, —N(RZ1)S(O)2RZ2, C6-10-aryl, and 5- to 10-membered heteroaryl,
• wherein RAX is hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —C(O)—C1-10-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, —C(O)—O—C1-10-alkyl, —C(O)—O—C6-10-aryl, —C(O)—O-heteroaryl, —C(O)—NRZ1RZ2, —S(O)2NRZ1RZ2, —S(O)2RZ1, C6-10-aryl, or 5- to 10-membered heteroaryl,
• wherein RAY is hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —C(O)—C1-10-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, C6-10-aryl, or 5- to 10-membered heteroaryl,
• wherein each of RZ1 and RZ2 are independently hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, C6-10-aryl, 5- to 10-membered heteroaryl, hydroxy, or C1-6-alkoxy;
• each RM is independently selected from the group consisting of hydrogen, C1-6-alkyl, trimethylsilyl, C6-10-aryl, 5- to 10-membered heteroaryl, arylalkyl, and —ORMX, wherein RMX is hydrogen, C1-6-alkyl, or C6-10-aryl;
• each R18 is independently selected from the group consisting hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, halogen, C6-10-aryl, and 5- to 10-membered heteroaryl;
• each R19 is independently selected from the group consisting hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, halogen, C6-10-aryl, and 5- to 10-membered heteroaryl;
• RD is selected from the group consisting of hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —C(O)—C1-10-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, —C(O)—O—C1-10-alkyl, —C(O)—O—C6-10-aryl, —C(O)—O-heteroaryl, —C(O)—NRZ1RZ2, C6-10-aryl, and 5- to 10-membered heteroaryl;
• and
• wherein any C6-10-aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, C1-6-alkyl, C1-6-haloalkyl, or C1-6-alkoxy.

A method for preparing a chiral tetracyclic compound, the chiral tetracyclic compound having a structure according to:

• the method comprising a step of:
• (ai) converting an unsaturated hydrindane to the chiral tetracyclic compound, wherein the unsaturated hydrindane has a structure corresponding to:
• (aii) converting a silyl-substituted hydrindane to the chiral tetracyclic compound, wherein the step is represented by the following scheme:
• wherein:
• RA is independently selected from the group consisting of hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, halogen, hydroxy, —ORAX, SRAY, —S(O)2NRZ1RZ2, —S(O)2RZ1, —S(O)RZ1, —NRZ1RZ2, —N(RZ1)C(O)RZ2, —N(RZ1)S(O)2RZ2, C6-10-aryl, and 5- to 10-membered heteroaryl,
• wherein RAX is C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —C(O)—C1-10-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, —C(O)—O—C1-10-alkyl, —C(O)—O—C6-10-aryl, —C(O)—O-heteroaryl, —C(O)—NRZ1RZ2, —S(O)2RZ1, C6-10-aryl, or 5- to 10-membered heteroaryl,
• wherein RAY is hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —C(O)—C1-10-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, C6-10-aryl, or 5- to 10-membered heteroaryl,
• wherein each of RZ1 and RZ2 are independently hydrogen, C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, C6-10-aryl, 5- to 10-membered heteroaryl, hydroxy, or C1-6-alkoxy;
• R11 is selected from the group consisting of hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, halogen, hydroxy, and ORCX,
• wherein RCX is C1-6-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, —C(O)—C1-10-alkyl, —C(O)—C6-10-aryl, —C(O)-heteroaryl, C6-10-aryl, or 5- to 10-membered heteroaryl;
• each R18 is independently selected from the group consisting hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, and halogen;
• each R19 is independently selected from the group consisting hydrogen, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-haloalkyl, and halogen;
• each RM is independently selected from the group consisting of hydrogen, C1-6-alkyl, trimethylsilyl, C6-10-aryl, 5- to 10-membered heteroaryl, arylalkyl, and —ORMX, wherein RMX is hydrogen, C1-6-alkyl, or C6-10-aryl;
• and
• X is halogen.

A method for preparing a compound having a C19 steroidal core skeleton of Formula (II):

• said C19 steroidal core skeleton having a quaternary center at each of carbon C10 and carbon C13, the method comprising a step of:
• (a) forging the steroidal C9-C10 bond via a stereoselective intramolecular reaction;
• and
• (b) performing an oxidative dearomatization reaction that is terminated by a suprafacial 1,2-shift with loss of a proton such that a substituent at position C9 is shifted to C10.