Method for making macrocycles
View Patent ↗Disclosed embodiments concern a method for making substantial quantities of desired macrocycles. Disclosed ring closing reactions make the macrocycle with desired olefin geometry in excellent yield and E/Z ratio. Particular embodiments of the current method concern intermediates that are obtained from commercially available starting materials in a small number of steps, thereby illustrating the commercial importance and applicability of the disclosed method. The macrocycle produced by the ring closing reaction can be further derivatized to provide analogs of the macrocyclic compounds.
1. A method for making a macrocycle, comprising:
providing an acyclic precursor; and
forming the macrocycle from the acyclic precursor, the macrocycle having a formula
where R 1 is selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, tert-butoxycarbonyl, 9H-fluoren-9-ylmethoxycarbonyl, allyloxycarbonyl, benzyloxy carbonyl, trichloroethoxycarbonyl, triphenylmethyl, and sulfonyl;
R 2 is selected from hydrogen and aliphatic;
each R 3 is independently selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, tert-butoxycarbonyl, 9H-fluoren-9-ylmethoxycarbonyl, allyloxycarbonyl, benzyloxy carbonyl, trichloroethoxycarbonyl, triphenylmethyl, and sulfonyl;
R 4 is selected from hydrogen, methyl, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 2 SCH 3 , benzyl, substituted benzyl, 3-indole, —CH(CH 3 ) 2 , —CH 2 OH, —CH(OH)(CH 3 ), —CH 2 C(O)NH 2 , —(CH 2 ) 2 C(O)NH 2 , —CH 2 SH, —CH 2 SeH, —(CH 2 ) 3 NHC(NH 2 + )NH 2 , —CH 2 (imidazole), —(CH 2 ) 4 NH 2 , —CH 2 C(O)OH, —(CH 2 ) 2 C(O)OH, and any natural or non-natural amino acid side chain;
or R 3 and R 4 individually are, or together form, a 5-membered ring;
R 5 is selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cyclic, substituted cyclic, ester, ether, formyl, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thioether, and thioester;
“----” indicates an optional double bond, having either Z or E geometry; and
each of R 6 and R 7 can be hydrogen when the optional double bond is present, or when the optional double bond is not present, each of R 6 and R 7 independently is selected from aliphatic, amino, halogen, hydrogen, and hydroxyl;
or R 6 and R 7 together form an epoxide or aziridine.
2. The method according to claim 1 where the acyclic precursor has a formula selected from
where R 1 is selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, substituted ketone, triphenylmethyl, and sulfonyl;
R 2 is selected from hydrogen and aliphatic;
each R 3 is independently selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, tert-butoxycarbonyl, 9H-fluoren-9-ylmethoxycarbonyl, allyloxycarbonyl, benzyloxy carbonyl, trichloroethoxycarbonyl, triphenylmethyl, and sulfonyl;
R 4 is selected from hydrogen, methyl, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 2 SCH 3 , benzyl, substituted benzyl, 3-indole, —CH(CH 3 ) 2, —CH 2 OH, —CH(OH)(CH 3 ), —CH 2 C(O)NH 2 , —(CH 2 ) 2 C(O)NH 2 , —CH 2 SH, —CH 2 SeH, —(CH 2 ) 3 NHC(NH 2 + )NH 2 , —CH 2 (imidazole), —(CH 2 ) 4 NH 2 , —CH 2 C(O)OH, —(CH 2 ) 2 C(O)OH, and any natural or non-natural amino acid side chain;
or R 3 and R 4 individually are, or together form, a 5-membered ring;
R 5 is selected from aliphatic, substituted aliphatic, alkoxy, particularly lower alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cyclic, substituted cyclic, ester, ether, formyl, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thioether, and thioester;
R 8 and R 9 independently are selected from —C(O)H, —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2 , —CH 2 P(O)(OEt) 2 , —CH 2 SO 2 -tetrazole, and —CR 10 ═CR 11 R 12 , where R 10 , R 11 , and R 12 independently are selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, and substituted arylalkyl;
“----” indicates an optional double bond, having either Z or E geometry; and
each of R 6 and R 7 can be hydrogen when the optional double bond is present, or when the optional double bond is not present, each of R 6 and R 7 independently is selected from aliphatic, amino, halogen, hydrogen, and hydroxyl;
or R 6 and R 7 together form an epoxide or aziridine.
3. The method according to claim 1 wherein forming the macrocycle comprises exposing the acyclic precursor to ring closing metathesis reagents selected from
4. The method according to claim 1 where the acyclic precursor has a formula
5. The method according to claim 1 where the acyclic precursor is selected from
6. The method according to claim 1 where the macrocycle is selected from
7. The method according to claim 1 , wherein providing the acyclic precursor comprises coupling a salicylic acid derivative with a dipeptide using peptide coupling conditions.
8. The method according to claim 7 where the dipeptide comprises naturally occurring amino acids, non-naturally occurring amino acids, and combinations thereof.
9. The method according to claim 7 where the dipeptide includes a glutamic acid derivative.
10. The method according to claim 7 where the dipeptide is formed by:
reacting a halogenated compound with a first amine compound to form a second amine compound, the halogenated compound having a formula
where R 8 is selected from —C(O)H, —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2, —CH 2 P(O)(OEt) 2 , —CH 2 SO 2 -tetrazole, and —CR 10 ═CR 11 R 12 , with R 10 , R 11 , and R 12 independently being selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, and substituted arylalkyl; and X is selected from I, Br, Cl, F;
the first amine compound having a formula
NH 2 R 1
where R 1 is selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, ester, ketone, substituted ketone, benzoyl, triphenylmethyl, and sulfonyl; and
subjecting the second amine compound to an amide bond formation reaction with a protected glutamic acid compound having a formula
wherein R 2 is selected from hydrogen or aliphatic, and PG is selected from arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, substituted ketone, triphenylmethyl, and sulfonyl.
11. The method according to claim 10 wherein the amide bond formation reaction comprises using an activating group selected from N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), carbonyl diimidazole (CDI), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU).
12. The method according to claim 7 where the salicylic acid derivative has a formula
13. The method according to claim 7 where the salicylic acid derivative is selected from
14. The method according to claim 10 wherein the dipeptide has a formula
15. The method according to claim 14 where the dipeptide is selected from
16. The method according to claim 7 further comprising forming an intermediate by performing a peptide coupling between the dipeptide and a protected amino acid derivative, wherein the intermediate has a formula
where R 1 is selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, substituted ketone, triphenylmethyl, and sulfonyl;
R 2 is selected from hydrogen and aliphatic;
each R 3 is independently selected from hydrogen, aliphatic, substituted aliphatic, alkyl, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, and ketone;
R 4 is selected from hydrogen, methyl, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 2 SCH 3 , benzyl, substituted benzyl, 3-indole, —CH(CH 3 ) 2 , —CH 2 OH, —CH(OH)(CH 3 ), —CH 2 C(O)NH 2 , —(CH 2 ) 2 C(O)NH 2 , —CH 2 SH, —CH 2 SeH, —(CH 2 ) 3 NHC(NH 2 + )NH 2 , —CH 2 (imidazole), —(CH 2 ) 4 NH 2 , —CH 2 C(O)OH, —(CH 2 ) 2 C(O)OH, and any natural or non-natural amino acid side chain;
or R 3 and R 4 individually are, or together form, a 5-membered ring;
R 8 is selected from —C(O)H, —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2, —CH 2 P(O)(OEt) 2 , —CH 2 SO 2 -tetrazole, and —CR 10 +CR 11 R 12 , with R 10 , R 11 , and R 12 independently being selected from hydrogen, aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl;
the dipeptide has a formula
and
the protected amino acid derivative has a formula
wherein PG is selected from arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, substituted ketone, triphenylmethyl, and sulfonyl.
17. The method according to claim 16 where the intermediate is selected from
18. The method according to claim 7 , further comprising:
reacting, under basic conditions, a salicylic acid with a halogenated compound to form a bis-substituted compound, the salicylic acid derivative having a formula
wherein R 5 is selected from aliphatic, substituted aliphatic, alkoxy, particularly lower alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cyclic, substituted cyclic, ester, ether, formyl, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thioether, and thioester;
the halogenated compound having a formula
wherein R 9 is selected from —C(O)H, —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2, —CH 2 P(O)(OEt) 2 , —CH 2 SO 2 -tetrazole, and —CR 10 ═CR 11 R 12 , with R 10 , R 11 , and R 12 independently being selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, and substituted arylalkyl; and X is selected from I, Br, Cl, and F, thereby forming the bis-substituted compound; and
hydrolyzing the bis-substituted compound to form a salicylic acid derivative having a formula
19. The method according to claim 16 where the protected amino acid derivative is selected from
20. The method according to claim 16 further comprising reacting the intermediate with the hydrolyzed salicylic acid derivative of claim 18 to provide an acyclic precursor having a formula
21. The method according to claim 1 wherein:
the acyclic precursor has a formula
and
forming the macrocycle comprises performing a ring closing reaction to close the acyclic precursor.
22. The method according to claim 21 where:
R 8 is —C(O)H; R 9 is selected from —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2 , —CH 2 P(O)(OEt) 2 , and —CH 2 SO 2 -tetrazole; or where R 9 is —C(O)H, and R 8 is selected from —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2 , —CH 2 P(O)(OEt) 2 , and —CH 2 SO 2 -tetrazole; and where the ring closing reaction is a ring closing olefination reaction selected from Wittig olefination, Horner-Wadsworth-Emmons olefination, Gennari-Still olefination, Julia-Lythgoe and Julia-Kocienski olefinations.
23. A compound having a formula
where:
R 1 is selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, substituted ketone triphenylmethyl, and sulfonyl;
R 2 is selected from hydrogen and aliphatic;
each R 3 is independently selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, substituted ketone;
R 4 is selected from hydrogen, methyl, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 2 SCH 3 , benzyl, substituted benzyl, 3-indole, —CH(CH 3 ) 2, —CH 2 OH, —CH(OH)(CH 3 ), —CH 2 C(O)NH 2 , —(CH 2 ) 2 C(O)NH 2 , —CH 2 SH, —CH 2 SeH, —(CH 2 ) 3 NHC(NH 2 + )NH 2 , —CH 2 (imidazole), —(CH 2 ) 4 NH 2 , —CH 2 C(O)OH, —(CH 2 ) 2 C(O)OH, and any natural or non-natural amino acid side chain;
or R 3 and R 4 individually are, or together form, a 5-membered ring;
R 5 is selected from aliphatic, substituted aliphatic, alkoxy, substituted alkoxy, amine, substituted amine, amide, substituted amide, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cyclic, substituted cyclic, ester, ether, formyl, halogen, heterocyclic, substituted heterocyclic, heteroaryl, substituted heteroaryl, hydrogen, hydroxyl, ketone, substituted ketone, nitro, nitroso, protecting groups, silyl, silyl ether, silyl ester, thiol, thioether, and thioester; and
R 8 is selected from —C(O)H, —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2 , —CH 2 P(O)(OEt) 2 , —CH 2 SO 2 -tetrazole, and —CR ═CR 11 R 12 , where R 10 , R 11 , and R 12 independently are selected from hydrogen, aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl; and if R 8 is —CR 10 ═CR 11 R 12 , then R 9 is —CR 10 ═CR 11 R 12 ; or if R 8 is —C(O)H, then R 9 is selected from —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2 , —CH 2 P(O)(OEt) 2 , and —CH 2 SO 2 -tetrazole; or if R 9 is —C(O)H, then R 8 is selected from —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2 , —CH 2 P(O)(OEt) 2 , and —CH 2 SO 2 -tetrazole.
24. The compound according to claim 23 wherein the compound is selected from
25. The method according to claim 1 further comprising chemically modifying the macrocycle via a palladium coupling reaction, a hydrogenation reaction, or an oxidation reaction.
26. The method according to claim 1 where forming the macrocycle comprises forming the macrocycle by ring closing amide bond formation, by ring closing metathesis, or by ring closing olefination.
27. A compound having a formula
where:
R 1 is selected from hydrogen, aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, substituted ketone, triphenylmethyl, and sulfonyl;
R 2 is selected from hydrogen and aliphatic;
each R 3 is independently selected from hydrogen, aliphatic, substituted aliphatic, alkyl, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, and ketone;
R 4 is selected from hydrogen, methyl, —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 2 SCH 3 , benzyl, substituted benzyl, 3-indole, —CH(CH 3 ) 2 , —CH 2 OH, —CH(OH)(CH 3 ), —CH 2 C( 0 )NH 2 , —(CH 2 ) 2 C(O)NH 2 , —CH 2 SH, —CH 2 SeH, —(CH 2 ) 3 NHC(NH 2+ )NH 2 , —CH 2 (imidazole), —(CH 2 ) 4 NH 2 , —CH 2 C(O)OH, —(CH 2 ) 2 C(O)OH, and any natural or non-natural amino acid side chain;
or R 3 and R 4 individually are, or together form, a 5-membered ring; and
R 8 is selected from —C(O)H, —CH 2 SO 2 Ph, —CH 2 PPh 3 , —CH 2 P(O)(OCH 2 CF 3 ) 2 , —CH 2 P(O)(OEt) 2 , —CH 2 SO 2 -tetrazole, and —CR 10 ═CR 11 R 12 , where R 10 ,R 11 , and R 12 independently are selected from hydrogen, aliphatic, aromatic, substituted aromatic, arylalkyl, and substituted arylalkyl.
28. A compound selected from
29. The compound according to claim 27 where R 1 is selected from aliphatic, substituted aliphatic, aromatic, substituted aromatic, arylalkyl, substituted arylalkyl, benzoyl, ester, ketone, substituted ketone, triphenylmethyl, and sulfonyl.
30. The compound according to claim 27 where R 2 is aliphatic.