Isocarbostyril alkaloids and functionalization thereof

A method of making an alkaloid compound of Formula VII:

• or a deuterium isotope thereof;
• wherein
• C is an sp3 carbon atom;
• is a single bond, or an optional double bond wherein two adjacent do not form consecutive double bonds;
• each Q2 is independently halo, —(C1-C6)alkyl, N(Ra)2, ORa, SRa, wherein each Ra is independently H or —(C1-C6)alkyl, or two adjacent Q2 optionally taken together form a ring;
• m is 0-3;
• R1 is halo, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, ORb, SRb, —C(═O)Rc, —S(═O)2Rc, cyano, nitro, phenyl, N(Rb)2, or a nitrogen heterocycle;
• wherein
• each Rb is independently H, —(C1-C6)alkyl, —C(═O)Rc, or optionally two Rb taken together form a heterocycle when R1 is N(Rb)2;
• and
• Rc is H, OH, —(C1-C6)alkyl, —O(C1-C6)alkyl, N(Rd)2, or phenyl, wherein
• each Rd is independently H or —(C1-C6)alkyl;
• and
• each R2 is independently H, halo, or ORe wherein each Re is independently H, —(C1-C6)alkyl, or a protecting group, or two adjacent R2 taken together optionally form an epoxide, or an alkylenedioxy group;
• R3 is H, —(C1-C6)alkyl, or —C(═O)Rc;
• and
• wherein each —(C1-C6)alkyl, —(C3-C6)cycloalkyl, phenyl and heterocycle are optionally substituted with or one or more substituents, each —(C1-C6)alkyl and —(C3-C6)cycloalkyl is saturated or optionally unsaturated, and each —(C1-C6)alkyl is unbranched or optionally branched;
• comprising:
• a) contacting a compound of Formula VIIB:
• or a deuterium isotope thereof;
• wherein M is H;
• and
• R2, R3, Q2 and m are as defined for Formula VII;
• and an organometallic regent to form an organometallic compound of Formula VIIB wherein M is a metal of the organometallic reagent;
• and
• b) quenching the organometallic compound with an electrophile, thereby forming the alkaloid compound of Formula VII.