Synthesis of polycyclic alkaloids

A method for making a polycyclic alkaloid, comprising:

• providing an aromatic amine compound having a formula
• and a carboxylic acid intermediate having a formula
• exposing the aromatic amine compound and the carboxylic acid compound to reaction conditions sufficient to form a hemiaminal intermediate having a formula
• exposing the hemiaminal intermediate to an acid to form a polycyclic alkaloid having a formula
• wherein
• R1 is selected from hydrogen, aliphatic, aryl, a heteroatom-containing moiety, or is bound to either R2 or R3, to form a four-, five-, or seven-membered cyclic aliphatic or a heterocycle;
• R2 and R3 independently are selected from hydrogen, aliphatic, aryl, aliphatic and bound to R1, heteroaliphatic and bound to R1, or, where R1 is hydrogen, R2 and R3 are aliphatic and bound together to form a five-, six-, or seven-membered cyclic aliphatic or a heterocycle;
• R4, R5, R6, R7, R8, and R9 independently are selected from aliphatic, aryl, halogen, a heteratom-containing moiety, hydrogen, or any combination thereof;
• R10, R1, R12, and R13 independently are selected from aliphatic, aryl, halogen, a heteroatom-containing moiety, hydrogen, and any combination thereof;
• R14, R15, and R16 independently are selected from aliphatic, aryl, halogen, a heteroatom-containing moiety, heteroaliphatic, heteroaryl, and hydrogen;
• or
• R14 and R15 or R15 and R16 are selected to form, together with the atom to which each is attached, a four-, five-, six-, or seven-membered cyclic alkane or alkene, or a five-, six-, or seven-membered aromatic ring;
• W is selected from oxygen, sulfur, and NR17 wherein R17 is selected from aliphatic, aryl, heteroaliphatic, heteroaryl, and hydrogen;
• Y is selected from —(CH2)—, —(CHR17)—, and —(CR17R18)—, oxygen, sulfur, any oxidized form of sulfur, and NR17 wherein R17 is selected from aliphatic, aryl, heteroaliphatic, heteroaryl, and hydrogen;
• V independently is selected from an sp3 or sp2 carbon atom, oxygen, sulfur, nitrogen, and NR17 wherein R17 is selected from aliphatic, aryl, heteroaliphatic, heteroaryl, and hydrogen, and any combination thereof;
• Z is selected from an sp3 or sp2 carbon atom, (CR17), or nitrogen;
• and
• m is zero or one.

A method for treating a disease or disorder associated with intestinal motility, or a disease/disorder associated with TGR5 receptors, bile acid receptors or G-protein coupled receptors, comprising administering an effective amount of a compound having a formula

• and salts, hydrates, solvates, and prodrugs thereof, wherein
• R1 is selected from hydrogen, aliphatic, aryl, a heteroatom-containing moiety, or is bound to either R2 or R3 to form a four-, five-, or seven-membered cyclic aliphatic or a heterocycle;
• R2 and R3 independently are selected from hydrogen, aliphatic, aryl, aliphatic and bound to R1, heteroaliphatic and bound to R1, or, where R1 is hydrogen, R2 and R3 are aliphatic and bound together to form a five-, six-, or seven-membered cyclic aliphatic or a heterocycle;
• R4, R5, R6, R7, R8, and R9 independently are selected from aliphatic, aryl, halogen, a heteratom-containing moiety, hydrogen, or any combination thereof;
• R10, R11, R12, and R13 independently are selected from aliphatic, aryl, halogen, a heteroatom-containing moiety, hydrogen, and any combination thereof;
• R14, R15, and R16 independently are selected from aliphatic, aryl, halogen, a heteroatom-containing moiety, heteroaliphatic, heteroaryl, and hydrogen;
• or
• R14 and R15 or R15 and R16 are selected to form, together with the atom to which each is attached, a four-, five-, six-, or seven-membered cyclic alkane or alkene, or a five-, six-, or seven-membered aromatic ring;
• W is selected from oxygen, sulfur, and NR17 wherein R17 is selected from aliphatic, aryl, heteroaliphatic, heteroaryl, and hydrogen;
• Y is selected from —(CH2)—, —(CHR17)—, and —(CR17R18)—, oxygen, sulfur, any oxidized form of sulfur, and NR17 wherein R17 is selected from aliphatic, aryl, heteroaliphatic, heteroaryl, and hydrogen;
• each V independently is selected from an sp3 or sp2 carbon atom, oxygen, sulfur, nitrogen, and NR17 wherein R17 is selected from aliphatic, aryl, heteroaliphatic, heteroaryl, and hydrogen, and any combination thereof;
• Z is selected from an sp3 or sp2 carbon atom, (CR17), or nitrogen;
• m is zero or one;
• wherein
• the disease or disorder associated with intestinal motility is selected from diverticulosis, megacolon, intestinal pseudoobstruction, constipation, dyspepsia, gastroparesis, irritable bowel syndrome, irritable bowel syndrome, small-intestinal diverticula, colonic diverticula, diverticulitis, painful diverticular disease without diverticulitis, hemorrhage from diverticula, aganglionic megacolon, chronic idiopathic megacolon, acquired megacolon, chronic or intermittent secondary pseudoobstruction, idiopathic intestinal pseudoobstruction, acute intestinal pseudoobstruction, and combinations thereof;
• and
• the disease/disorder associated with TGR5 receptors, bile acid receptors or G-protein coupled receptors is selected from cholelithiasis, cerebrotendinous xanthomatosis, primary biliary cirrhosis, non-alcoholic fatty liver disease, hypertriglyceridaemia, hypercholesterolaemia, skin cancer, lung cancer, colon cancer, metabolic diseases, 3b-hydroxysteroid oxido-reductase deficiency, and combinations thereof.