Synthesis of polycyclic alkaloids

1. A compound having a formula

wherein

R 1 is bound to either R 2 or R 3 to form a cyclopentyl ring and the other of R 2 and R 3 is selected from hydrogen, C 1-10 alkyl, aryl;

R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are selected from hydrogen, C 1-10 alkyl, aryl, halogen, a heteroatom-containing moiety, or any combination thereof;

R 10 , R 11 , R 12 , and R 13 independently are selected from C 1-10 alkyl, aryl, halogen, a heteroatom-containing moiety, hydrogen, and any combination thereof;

W is selected from oxygen, sulfur, and NR 17 wherein R 17 is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof;

Y is selected from —(CH 2 )—, —(CHR 17 )—, and —(CR 17 R 18 )—, oxygen, sulfur, any oxidized form of sulfur, and NR 17 wherein R 17 is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof; and

m is zero or one;

wherein each heteroatom-containing moiety independently is selected from —C(O)H; —C(O)X, where X is selected from fluorine, chlorine, bromine, and iodine; —OC(O)(OR b ); —C(O)OH; —OR b ; —C(O)OR b ; —OH; —C(O)R b ; —OSi(R b )(R c )R d ; —OOR b ; —OOH; —OP(O)(OH) 2 ; —P(O)(OH) 2 ; —OP(O)(OR b )OH; —PR b R c ; —SH; —SR b ; —SSR b ; —S(O)R b ; —SO 2 R b ; —C(S)R b ; —C(S)H; —S(O)OH; —SO 3 H; —SCN; —NCS; -5-oxazole; -4-oxazole; -2-oxazole; -5-1,2,3-oxadiazole; -2-1,3,4-oxadiazole; -4-1,2,3-oxadiazole; -2-1H-imidazole; -4-1H-imidazole; -5-1H-imidazole; -4-1H-1,2,3-triazole; -5-1H-1,2,3-triazole; -5-1H-tetrazole; -5-isoxazole; -4-isoxazole; -3-isoxazole; —C(O)N(R b ) 2 ; —N 3 ; —NNR b ; —OCN; —NCO; —C(O)NR b C(O)R b ; —CN; —N + C − ; —NO 2 ; —NO; —CH 2 NO 2 ; —NH 2 ; —NHR b ; —N(R b ) 2 ; or any combination thereof, and wherein each R b and R c independently is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof.

2. The compound according to claim 1 having a formula

wherein R 19 and R 20 independently are selected from C 1-10 alkyl, halogen, hydrogen, a Gi 10 heteroatom-containing moiety, or any combination thereof, n is 1, Y is CHR 17 , and wherein the heteroatom-containing moiety is selected from —C(O)H; —C(O)X, where X is selected from fluorine, chlorine, bromine, and iodine; —OC(O)(OR b ); —C(O)OH; —OR b ; —C(O)OR b ; —OH; —C(O)R b ; —OSi(R b )(R c )R d ; —OOR b ; —OOH; —OP(O)(OH) 2 ; —P(O)(OH) 2 ; —OP(O)(OR b )OH; —PR b R c ; —SH; —SR b ; —SSR b ; —S(O)R b ; —SO 2 R b ; —C(S)R b ; —C(S)H; —S(O)OH; —SO 3 H; —SCN; —NCS; -5-oxazole; -4-oxazole; -2-oxazole; -5-1,2,3-oxadiazole; -2-1,3,4-oxadiazole; -4-1,2,3-oxadiazole; -2-1H-imidazole; -4-1H-imidazole; -5-1H-imidazole; -4-1H-1,2,3-triazole; -5-1H-1,2,3-triazole; -5-1H-tetrazole; -5-isoxazole; -4-isoxazole; -3-isoxazole; —C(O)N(R b ) 2 ; —N 3 ; —NNR b ; —OCN; —NCO; —C(O)NR b C(O)R b ; —CN; —N + C − ; —NO 2 ; —NO; —CH 2 NO 2 ; —NH 2 ; —NHR b ; —N(R b ) 2 ; or any combination thereof, and wherein each R b and R c independently is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof.

3. The compound according to claim 1 having a formula

wherein R 20 and R 21 independently are selected from C 1-10 alkyl, halogen, hydrogen, a heteroatom-containing moiety, or any combination thereof; wherein the heteroatom-containing moiety is selected from C(O)H; —C(O)X, where X is selected from fluorine, chlorine, bromine, and iodine; —OC(O)(OR b ); —C(O)OH; —OR b ; —C(O)OR b ; —OH; —C(O)R b ; —OSi(R b )(R c )R d ; —OOR b ; —OOH; —OP(O)(OH) 2 ; —P(O)(OH) 2 ; —OP(O)(OR b )OH; —PR b R c ; —SH; —SR b ; —SSR b ; —S(O)R b ; —SO 2 R b ; —C(S)R b ; —C(S)H; —S(O)OH; —SO 3 H; —SCN; —NCS; -5-oxazole; -4-oxazole; -2-oxazole; -5-1,2,3-oxadiazole; -2-1,3,4-oxadiazole; -4-1,2,3-oxadiazole; -2-1H-imidazole; -4-1H-imidazole; -5-1H-imidazole; -4-1H-1,2,3-triazole; -5-1H-1,2,3-triazole; -5-1H-tetrazole; -5-isoxazole; -4-isoxazole; -3-isoxazole; —C(O)N(R b ) 2 ; —N3; —NNR b ; —OCN; —NCO; —C(O)NR b C(O)R b ; —CN; —N + C − ; —NO 2 ; —NO; —CH 2 NO 2 ; —NH 2 ; —NHR b ; —N(R b ) 2 ; or any combination thereof, and wherein each R b and R c independently is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof.

4. The compound according to claim 1 wherein the compound is selected from

5. 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

R 1 is bound to either R 2 or R 3 to form a cyclopentyl ring and the other of R 2 and R 3 is selected from hydrogen, C 1-10 alkyl, or aryl;

R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are selected from C 1-10 alkyl, aryl, hydrogen, halogen, a heteroatom-containing moiety, or any combination thereof;

R 10 , R 11 , R 12 , and R 13 independently are selected from C 1-10 alkyl, aryl, hydrogen, halogen, a heteroatom-containing moiety, and any combination thereof;

W is selected from oxygen, sulfur, and NR 17 wherein R 17 is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof;

Y is selected from —(CH 2 )—, —(CHR 17 )—, and —(CR 17 R 18 )—, oxygen, sulfur, any oxidized form of sulfur, and NR 17 wherein R 17 is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof; and

m is zero or one; and

wherein each heteroatom-containing moiety independently is selected from —C(O)H; —C(O)X, where X is selected from fluorine, chlorine, bromine, and iodine; —OC(O)(OR b ); —C(O)OH; —OR b ; —C(O)OR b ; —OH; —C(O)R b ; —OSi(R b )(W)R d ; —OOR b ; —OOH; —OP(O)(OH) 2 ; —P(O)(OH) 2 ; —OP(O)(OR b )OH; —PR b R c ; —SH; —SR b ; —SSR b ; —S(O)R b ; —SO 2 R b ; —C(S)R b ; —C(S)H; —S(O)OH; —SO 3 H; —SCN; —NCS; -5-oxazole; -4-oxazole; -2-oxazole; -5-1,2,3-oxadiazole; -2-1,3,4-oxadiazole; -4-1,2,3-oxadiazole; -2-1H-imidazole; -4-1H-imidazole; -5-1H-imidazole; -4-1H-1,2,3-triazole; -5-1H-1,2,3-triazole; -5-1H-tetrazole; -5-isoxazole; -4-isoxazole; -3-isoxazole; —C(O)N(R b ) 2 ; —N3; —NNR b ; —OCN; —NCO; —C(O)NR b C(O)R b ; —CN; —N + C − ; —NO 2 ; —NO; —CH 2 NO 2 ; —NH 2 ; —NHR b ; —N(R b ) 2 ; or any combination thereof, and wherein each R b and R c independently is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof.

6. The method according to claim 5 wherein the aromatic amine compound is selected from

7. The method according to claim 5 wherein the carboxylic acid compound is

8. The method according to claim 5 wherein the one or more activating reagents are selected from N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyl diimidazole, 1-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, and any combination thereof, the base is selected from triethylamine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, and diisopropylethylamine, and the solvent is dichloromethane.

9. The method according to claim 5 wherein the hemiaminal intermediate is selected from

10. The method according to claim 5 wherein the acid is selected from para-toluenesulfonic acid, trifluoroacetic acid, and camphorsulfonic acid.

11. The method according to claim 5 wherein the polycyclic alkaloid is selected from