Diazene directed modular synthesis of compounds with quaternary carbon centers
Diazene-directed modular synthesis is described for the preparation Csp2-Csp3 and Csp3-Csp3 linkages where one or more stereogenic quaternary carbon centers are formed. The disclosed methods are directed to the preparation of compounds of Formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, from compounds of Formula (II): wherein R 1 -R 5 and q are as defined independently for each occurrence herein. A wide variety of compounds can be accessed in this manner, including oligocyclotryptamines, where the stereochemistry of each subunit is beneficially secured before fragment coupling.
1. A method of preparing a compound of Formula (II′):
or a salt, tautomer, or stereoisomer thereof, comprising reacting a compound of Formula (III′), or a salt, tautomer, or stereoisomer thereof, and a compound of Formula (IV′), or a salt, tautomer, or stereoisomer thereof:
wherein:
R 1 is alkenyl, aryl, or heteroaryl;
zero, one, two, or three of (i) R 3 and R 4 , (ii) R 3 and R 5 , and (iii) R 4 and R 5 taken together with the carbon atoms to which they are attached independently form a substituted or unsubstituted, 5-14 membered ring, and the remaining R 3 , R 4 , and/or R 5 are independently absent, alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, provided that each of R 4 and R 5 is not absent;
each instance of R 11 and R 12 is independently selected from H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, wherein R 11 and R 12 taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring;
each instance of R 13 and R 14 is independently selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —OR 11 , —(CH 2 ) r SiMe 3 , or —(CH 2 ) r R 11 ;
each instance of R 15 is independently —S(═O) p R 13 , —S(═O) 2 NR 11 R 12 , —C(═O)R 13 , —C(═O)R 20 , —C(═O)O(CH 2 ) r R 20 , —C(═O)CF 3 , —C(═O)OR 20 , —P(═O)R 13 R 14 , or, —P(═O)NR 11 R 12 ;
each instance of R 16 is independently I, Br, Cl, —OH, —OSO 2 CF 3 , —OS(O) 2 R 13 , —OP(═O)R 13 R 14 , —OC(═NR 11 )R 12 , —OC(═NR 11 )CCl 3 , —OR 11 , or —N 2 + X − , wherein X − is halogen;
each instance of R 20 is independently —Si(alkyl) 3 , —Si(alkyl) 2 aryl, or Si(aryl) 2 alkyl;
each instance of p is independently 1 or 2; and
each instance of r is independently an integer from 1 to 4.
2. The method of claim 1 , wherein a compound of Formula (II′), or a salt, tautomer, or stereoisomer thereof, is of the formula:
or a salt, tautomer, or stereoisomer thereof, and a compound of Formula (IV′), or a salt, tautomer, or stereoisomer thereof, is of the formula:
or a salt, tautomer, or stereoisomer thereof, wherein:
Ring A is a substituted or unsubstituted, 5-14 membered ring;
----- is a single bond or absent;
R 3 is absent, alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or R 3 is fused to Ring A to additionally form a substituted or unsubstituted, 5-14 membered ring;
R 22 is absent, hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —N═N-aryl, —N═N-heteroaryl, —N═N-carbocyclyl, or —N═N-heterocyclyl.
3. The method of claim 2 , wherein a compound of Formula (IV′-A), or a salt, tautomer, or stereoisomer thereof, is of the formula:
Formula (IV′-B) or a salt, tautomer, or stereoisomer thereof, wherein:
each instance of R 6 is independently halogen, —OH, —OR 11 , —OC(═O)R 11 , —NR 11 R 12 , —S(═O) p R 13 , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 NR 12 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or two R 6 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring;
each instance of R 8 and R 9 is independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —SR 11 , —S(═O) p R 13 , —S(═O) 2 NR 11 R 12 , —C(═O)O(CH 2 ) o R 11 , aryl, heteroaryl, carbocyclyl, heterocyclyl, —C(═O)OCH 2 CH 2 Si(CH 3 ) 3 , or nitrogen protecting group;
each instance of R 10 is independently selected from H, C 1 -C 12 alkyl; C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —S(═O) p R 13 , —OH, —OR 11 , —OC(═O)R 11 , —NR 11 R 12 , aryl, heteroaryl, carbocyclyl, or heterocyclyl, or two R 10 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring;
each instance of o is independently an integer from 0 to 4; and
each instance of m is an integer from 0 to 3.
4. The method of claim 1 , wherein the compound of Formula (III′), or a salt, tautomer, or stereoisomer thereof, is of the formula:
or a salt, tautomer, or stereoisomer thereof, wherein:
Ring B is a substituted or unsubstituted, 5-14 membered ring;
each instance of R 6 is independently halogen, —OH, —OR 11 , —OC(═O)R 11 , —NR 11 R 12 , —S(═O) p R 13 , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 NR 12 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or two R 6 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring; and
r is an integer from 0 to 5.
5. The method of claim 4 , wherein the compound of Formula (III′), or a salt, tautomer, or stereoisomer thereof, is of the formula:
or a salt, tautomer, or stereoisomer thereof, wherein Ring B′ is a substituted or unsubstituted, 5-14 membered ring comprising two or more carbon atoms in the ring system.
6. The method of claim 1 , wherein the compound of Formula (III′), or a salt, tautomer, or stereoisomer thereof, is of the formula:
or a salt, tautomer, or stereoisomer thereof, wherein:
each instance of R 6 is independently halogen, —OH, —OR 11 , —OC(═O)R 11 , —NR 11 R 12 , —S(═O) p R 13 , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 NR 12 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or two R 6 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring;
each instance of R 8 and R 9 is independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —SR 11 , —S(═O) p R 13 , —S(═O) 2 NR 11 R 12 , —C(═O)O(CH 2 ) o R 11 , aryl, heteroaryl, carbocyclyl, heterocyclyl, —C(═O)OCH 2 CH 2 Si(CH 3 ) 3 , or nitrogen protecting group;
each instance of R 10 is independently H, C 1 -C 12 alkyl; C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —S(═O) p R 13 , —OH, —OR 11 , —OC(═O)R 11 , —NR 11 R 12 , aryl, heteroaryl, carbocyclyl, or heterocyclyl, or two R 10 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring;
R 17 is H, —OH, —OR 11 , —NR 11 R 12 , aryl, heteroaryl, carbocyclyl, heterocyclyl,
R 19 is selected from H, alkyl, alkenyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and
R 7 is H, —N 3 , —N(R 15 )NH 2 , —NHR 15 , hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —N═N-aryl, —N═N-heteroaryl, —N═N-carbocyclyl, or —N═N-heterocyclyl;
R 23 is absent, hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —N═N-aryl, —N═N-heteroaryl, —N═N-carbocyclyl, or —N═N-heterocyclyl;
m is an integer from 0 to 3; and
n and o are each independently an integer from 0 to 4.
7. The method of claim 1 further comprising reacting a compound of Formula (II′):
or a salt, tautomer, or stereoisomer thereof, by extruding one or more equivalents of dinitrogen.
8. The method of claim 7 , wherein the product of reacting a compound of Formula (II′), or a salt, tautomer, or stereoisomer thereof, is a compound of Formula (I′):
or a salt, tautomer, or stereoisomer thereof.
9. The method of claim 8 , wherein the compound of Formula (I′), or a salt, tautomer, or stereoisomer thereof, is of the formula:
or a salt, tautomer, or stereoisomer thereof, wherein:
R 22 is absent, hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —N═N-aryl, —N═N-heteroaryl, —N═N-carbocyclyl, or —N═N-heterocyclyl;
Ring A is a substituted or unsubstituted, 5-14 membered ring;
---- is a single bond or absent;
R 3 is absent, alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or R 3 is fused to Ring A to additionally form a substituted or unsubstituted, 5-14 membered ring;
Ring B is a substituted or unsubstituted, 5-14 membered ring;
each instance of R 6 is independently halogen, —OH, —OR 11 , —OC(═O)R 11 , —NR 11 R 12 , —S(═O) p R 13 , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 NR 12 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or two R 6 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring; and
r is an integer from 0 to 5.
10. The method of claim 9 , wherein the compound of Formula (I′), or a salt, tautomer, or stereoisomer thereof, is:
or a salt, tautomer, or stereoisomer thereof, wherein:
each instance of R 6 is independently halogen, —OH, —OR 11 , —OC(═O)R 11 , —NR 11 R 12 , —S(═O) p R 13 , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 NR 12 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or two R 6 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring;
each instance of R 8 and R 9 is independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —SR 11 , —S(═O) p R 13 , —S(═O) 2 NR 11 R 12 , —C(═O)O(CH 2 ) o R 11 , aryl, heteroaryl, carbocyclyl, heterocyclyl, —C(═O)OCH 2 CH 2 Si(CH 3 ) 3 , or nitrogen protecting group;
each instance of R 10 is independently selected from H, C 1 -C 12 alkyl; C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —S(═O) p R 13 , —OH, —OR 11 , —OC(═O)R 11 , —NR 11 R 12 , aryl, heteroaryl, carbocyclyl, or heterocyclyl, or two R 10 groups taken together with the carbon atoms to which they are attached form an aryl, heteroaryl, carbocyclic, or heterocyclic ring;
each instance of o is independently an integer from 0 to 4;
each instance of m is an integer from 0 to 3;
each instance of R 22 is independently absent, hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —N═N-aryl, —N═N-heteroaryl, —N═N-carbocyclyl, or —N═N-heterocyclyl;
R 17 is H, —OH, —OR 11 , —NR 11 R 12 , aryl, heteroaryl, carbocyclyl, heterocyclyl,
R 19 is selected from H, alkyl, alkenyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and
R 7 is H, —N 3 , —N(R 15 )NH 2 , —NHR 15 , hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —N═N-aryl, —N═N-heteroaryl, —N═N-carbocyclyl, or —N═N-heterocyclyl; and
R 23 is absent, hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —N═N-aryl, —N═N-heteroaryl, —N═N-carbocyclyl, or —N═N-heterocyclyl.
11. The method of claim 7 , wherein the product of reacting a compound of Formula (II′), or a salt, tautomer, or stereoisomer thereof, is of the formula:
or a salt, tautomer, or stereoisomer thereof.
12. The method of claim 2 , wherein:
Ring A is a substituted or unsubstituted, 5-14 membered ring, saturated, unsaturated, or aromatic, carbocyclic ring or a substituted or unsubstituted, 5-14 membered, saturated, unsaturated, or aromatic, heterocyclic ring;
R 3 is absent, alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or R 3 is fused to Ring A to additionally form a substituted or unsubstituted, 5-14 membered, saturated, unsaturated, or aromatic, carbocyclic ring or a substituted or unsubstituted, 5-14 membered, saturated, unsaturated, or aromatic, heterocyclic ring.
13. The method of claim 3 , wherein:
R 22
or
; and
R 23 is absent, hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, —N═N-aryl, —N═N-heteroaryl, —N═N-carbocyclyl, or —N═N-heterocyclyl.
14. The method of claim 4 , wherein the compound of Formula (III') or a salt, tautomer, or stereoisomer thereof, is of the formula:
or a salt, tautomer, or stereoisomer thereof, wherein V, W, X, Y, and Z are each independently —CH or N.
15. The method of claim 4 , wherein the compound of Formula (III'), or a salt, tautomer, or stereoisomer thereof, is of the formula:
, or a salt, tautomer, or stereoisomer thereof, wherein R, S, and T are each independently —CH or N; and
U is O, S, or NR 11 , wherein R 11 is independently H, Ci-C 12 alkyl, C 2 - C12 alkenyl, C 2 -C 12 alkynyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl; and
n is an integer from 0 to 4.
16. The method of claims 7 , wherein the reaction by extruding one or more equivalents of dinitrogen is a radical recombination reaction.
17. The method of claim 16 , wherein the reaction by extruding one or more equivalents of dinitrogen is carried out by irradiation.
18. The method of claim 1 , wherein the reaction of a compound of Formula (III'), or a salt, tautomer, or stereoisomer thereof, and a compound of Formula (IV'), or a salt, tautomer, or stereoisomer thereof, comprises an electrophilic activation of a compound of Formula (IV'), or a salt, tautomer, or stereoisomer thereof.
19. The method of claim 18 , wherein the electrophilic activation comprises reaction of the compound of Formula (IV'), or a salt, tautomer, or stereoisomer thereof, with a silver (I) salt, and a base.
20. The method of claim 19 , wherein the compound of Formula (III'), or a salt, tautomer, or stereoisomer thereof, is resistant to oxidation by the silver (I) salt.