Convergent and enantioselective total synthesis of Communesin analogs
A highly convergent biomimetic synthesis of a complex polycyclic scaffold has been successfully implemented. From these efforts, compounds having a structure of Formula (I): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 -R 8 and m, n, r, s, t, and u are as defined herein, is provided. Methods of making such compounds are also disclosed as are methods for the treatment of cancer, various infectious diseases, and abnormal cardiovascular function.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
R 1 and R 4 are each independently selected from H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 9 , —C(═O)NR 9 R 10 , —S(═O) u R 12 , aryl, heteroaryl, carbocyclyl, and heterocyclyl;
R 3 is selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 9 , —C(═O)NR 9 R 10 , —S(═O) u R 12 , aryl, heteroaryl, carbocyclyl, and heterocyclyl, or R 3 and R 4 taken together with the atoms to which they are attached form a heteroaryl or heterocyclic ring;
R 2 and R 5 are each independently selected from F, Cl, Br, I, —OH, —OR 9 , —OC(═O)R 9 , —S(═O) u R 12 , —NR 9 R 10 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl;
R 6 is H, —OH, —OR 9 , —OC(═O)R 9 , —S(═O) u R 12 , —NR 9 R 10 , C 1 -C 12 alkyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl;
R 7 and R 8 are each independently selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 9 , —C(═O)NR 9 R 10 , —S(═O) u R 12 , —OH, —OR 9 , —OC(═O)R 9 , —NR 9 R 10 , aryl, heteroaryl, carbocyclyl, and heterocyclyl, or two R 7 or two R 8 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring;
R 9 and R 10 are each independently selected from H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl, or R 9 and R 10 taken together with the atoms to which they are attached form a heteroaryl or heterocyclic ring;
each instance of R 12 is independently C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —(CH 2 ) n SiMe 3 , or —(CH 2 ) n R 9 ;
m and t are each independently an integer from 0 to 3, inclusive;
n, r, and s are each independently an integer from 0 to 4, inclusive;
u′ is 0, 1, or 2;
each instance of u is independently 0, 1, or 2; and
each of the C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, carbocyclic ring, heterocyclyl, and heterocyclic ring is independently optionally substituted.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 is H, C 1 -C 12 alkyl, C 1 -C 12 alkenyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 4 is H, —C(═O)R 9 , C 1 -C 12 alkyl, aryl, or heteroaryl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 3 is C 1 -C 12 alkyl or —S(═O) u R 12 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 and R 5 are each independently F, Br, Cl, I, C 1 -C 12 alkyl, aryl, or heteroaryl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 is
or
and wherein X is O, NR 9 , or —S(═O) u R 12 , and v is an integer from 0 to 4, inclusive.
7. The compound of claim 6 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 is —C(═O)R 9 .
8. The compound of claim 7 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 9 is Me, Et, n-Pr,
or
9. The compound of claim 8 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 is
10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
11. A method of making a compound of Formula (I):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
R 1 , R 3 , and R 4 are each independently selected from H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 9 , —C(═O)NR 9 R 10 , —S(═O) u R 12 , aryl, heteroaryl, carbocyclyl, and heterocyclyl, or R 3 and R 4 taken together with the atoms to which they are attached form a heteroaryl or heterocyclic ring;
R 2 and R 5 are each independently selected from F, Cl, Br, I, —OH, —OR 9 , —OC(═O)R 9 , —S(═O) u R 12 , —NR 9 R 10 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl;
R 6 is H, —OH, —OR 9 , —OC(═O)R 9 , —S(═O) u R 12 , —NR 9 R 10 , C 1 -C 12 alkyl, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl;
R 7 and R 8 are each independently selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 9 , —C(═O)NR 9 R 10 , —S(═O) u R 12 , —OH, —OR 9 , —OC(═O)R 9 , —NR 9 R 10 , aryl, heteroaryl, carbocyclyl, and heterocyclyl, or two R 7 or two R 8 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring:
R 9 and R 10 are each independently selected from H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, and heterocyclyl, or R 9 and R 10 taken together with the atoms to which they are attached form a heteroaryl or heterocyclic ring;
each instance of R 12 is independently C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —(CH 2 ) n SiMe 3 , or —(CH 2 ) n R 9 ;
m and t are each independently an integer from 0 to 3, inclusive;
n, r, and s are each independently an integer from 0 to 4, inclusive;
u′ is 0, 1, or 2;
each instance of u is independently 0, 1, or 2; and
each of the C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, carbocyclic ring, heterocyclyl, and heterocyclic ring is independently optionally substituted:
with the proviso that the compound is not of the formula:
comprising forming a bond between the nitrogen atom at position N1 and the carbon atom at position C 8 a′, and a bond between the nitrogen atom at position N8′ and the carbon atom at position C 8 a in a compound of Formula (V):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 13 is
and R 4 is —CN, —OH, —OR 9 , —NR 9 R 10 , —S(O) u R 12 , or —P(O)(OR 9 ) 2 .
12. The method of claim 11 further comprising a radical recombination reaction of a compound of Formula (VI):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, to form the compound of Formula (V), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
13. The method of claim 12 further comprising the extrusion of sulfur dioxide from a compound of Formula (VII):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, to form the compound of Formula (VI), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
14. The method of claim 13 further comprising reacting a compound of Formula (III), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; and a compound of Formula (VIII), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:
to form the compound of Formula (VII), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
15. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 is heterocyclyl.
16. The compound of claim 6 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 is
X is O, and v is 0.
17. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 is C 2 -C 12 alkenyl.
18. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 is
19. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 3 is —S(═O) u R 12 .
20. The compound of claim 19 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein u is 2.
21. The compound of claim 20 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 12 is —(CH 2 ) n SiMe 3 .
22. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 4 is C 1 -C 12 alkyl.
23. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein t is 1.
24. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein u′ is 1.