Aziridine aldehydes, aziridine-conjugated amino derivatives, aziridine-conjugated biomolecules and processes for their preparation
View Patent ↗The present invention relates to unprotected amino aldehydes and applications for same. More particularly, the present invention relates to novel aziridine aldehydes and processes for preparing these novel compounds. The invention also relates to aziridine-conjugated amino derivatives, and processes for preparing the same. Pentacyclic compounds may be prepared using the aziridine aldehydes of the present invention, and the invention relates to these compounds and the processes by which they are made. The invention also relates to aziridine-conjugated bioactive molecules, such as amino acids and peptides, and processes for preparing such compounds.
1. A compound of formula (Ia):
wherein n=0 or 1, and R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from H; lower alkyl; aryl; heteroaryl; alkenyl; cycloalkyl; heterocycle; esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl; amides of the formula —C(O)NR**R***, wherein R** and R*** are independently selected from alkyl and aryl; —CH 2 C(O)R, wherein R is selected from —OH, lower alkyl, aryl, -loweralkyl-aryl, or —NR a R b , where R a and R b are independently selected from H, lower alkyl, aryl or -loweralkyl-aryl; —C(O)R c , wherein R c is selected from lower alkyl, aryl or -loweralkyl-aryl; or -lower alkyl-OR d , wherein R d is a suitable protecting group;
all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents,
with the proviso that when R 2 is phenyl, R 3 is methyl, and n=0 then R 1 cannot be —C(O)NEt 2 .
2. A compound as claimed in claim 1 wherein n=0, R 1 and R 3 are independently selected from H; aryl; heteroaryl; and -lower alkyl-OR d , wherein R d is a suitable protecting group, and R 2 is selected from H and aryl.
3. A compound as claimed in claim 1 selected from the group consisting of:
4. A process for producing a compound of formula (Ia) and/or (Ib) as defined in claim 1 wherein the process is selected from any one of the following processes on the basis of compatibility of groups R 1 , R 2 , R 3 , R 4 , and R 5 with said process:
(a) reacting a compound of the formula (IIa)
wherein n, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1 and X is selected from
wherein Y is oxygen or nitrogen, and
when Y is oxygen, R 6b is absent, and R 6a is selected from lower alkyl; aryl;
and -loweralkyl-aryl, and
when Y is nitrogen, R 6a and R 6b are independently selected from hydrogen, lower alkyl; alkoxy; aryl; and -loweralkyl-aryl;
with a hydride transfer reagent to form the compound of formula (Ia) and/or (Ib) as defined in claim 1 ;
(b) reducing a compound of formula (IIb)
wherein n, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1 to produce the compound of formula (Ia) and/or (Ib) as defined in claim 1 ;
(c) Fukuyama reduction of a compound of formula (IIc)
wherein n, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1 and
R* is selected from aryl; alkyl; heteroaryl; and heteroalkyl;
to produce the compound of formula (Ia) and/or (Ib) as defined in claim 1 ;
(d) oxidative cleavage of a compound of formula (IId)
wherein n, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1 to produce the compound of formula (Ia) and/or (Ib) as defined in claim 1 ;
(e) oxidation of a compound of formula (IIe)
wherein n, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1 to produce the compound of formula (Ia) and/or (Ib) as defined in claim 1 ; and
(f) oxidative cleavage of a compound of formula (IIf)
wherein n, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1 to produce the compound of formula (Ia) and/or (Ib) as defined in claim 1 .
5. The process of claim 4 wherein process (a) is selected and X is
wherein R 6a is selected from lower alkyl; aryl; and -loweralkyl-aryl.
6. The process of claim 5 wherein the hydride transfer reagent used in said process is diisobutylaluminum hydride.
7. A method for preparing an aziridine-conjugated bioactive molecule selected from an amino acid and peptide comprising coupling a suitably protected amino acid or peptide having a free amino group to a compound of formula (Ia) as defined in claim 1 via reductive amination to form the aziridine-conjugated amino acid or peptide.
8. The process of claim 7 wherein the reductive amination conditions are selected from the following based on the solubility and stability of the bioactive molecule under said conditions:
NaCNBH 3 , methanol, acetic acid (1% in methanol);
NaCNBH 3 , methanol;
NaCNBH 3 /Ce(SO 4 ) 2 , methanol/dichloromethane (1/1);
NaCNBH 3 /PbBr 2 , methanol/dichloromethane (1/1);
NaCNBH 3 /ZnCl 2 , methanol/dichloromethane (1/1);
NaCNBH 3 /ZnCl 2 , methanol/tetrahydrofuran (1/1);
NaCNBH 3 /ZnCl 2 , methanol/diethyl ether (1/1); and
NaCNBH 3 /ZnCl 2 , methanol/toluene (1/1).
9. The process of claim 7 wherein the bioactive molecule is a suitably protected amino acid and the reductive amination conditions are NaCNBH 3 /ZnCl 2 , methanol/tetrahydrofuran (1/1).
10. An aziridine-conjugated amino acid or peptide prepared by the process of claim 7 .
11. A compound as claimed in claim 1 , wherein R 1 is selected from lower alkyl; aryl; heteroaryl; alkenyl; cycloalkyl; heterocycle; esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl; amides of the formula —C(O)NR**R***, wherein R** and R*** are independently selected from alkyl and aryl; —CH 2 C(O)R, wherein R is selected from —OH, lower alkyl, aryl, -loweralkyl-aryl, or —NR a R b , where R a and R b are independently selected from H, lower alkyl, aryl or -loweralkyl-aryl; —C(O)R c , wherein R c is selected from lower alkyl, aryl or -loweralkyl-aryl; or -lower alkyl-OR d , wherein R d is a suitable protecting group; all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents.
12. A compound as claimed in claim 1 , wherein R 2 is selected from lower alkyl; aryl; heteroaryl; alkenyl; cycloalkyl; heterocycle; esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl; amides of the formula —C(O)NR**R***, wherein R** and R*** are independently selected from alkyl and aryl; —CH 2 C(O)R, wherein R is selected from —OH, lower alkyl, aryl, -loweralkyl-aryl, or NR a R b , where R a and R b are independently selected from H, lower alkyl, aryl or -loweralkyl-aryl; —C(O)R c , wherein R c is selected from lower alkyl, aryl or -loweralkyl-aryl; or -lower alkyl-OR d , wherein R d is a suitable protecting group;
all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents.
13. A compound as claimed in claim 1 , wherein R 3 is selected from lower alkyl; aryl; heteroaryl; alkenyl; cycloalkyl; heterocycle; esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl; amides of the formula —C(O)NR**R***, wherein R** and R*** are independently selected from alkyl and aryl; —CH 2 C(O)R, wherein R is selected from —OH, lower alkyl, aryl, -loweralkyl-aryl, or NR a R b , where R a and R b are independently selected from H, lower alkyl, aryl or -loweralkyl-aryl; —C(O)R c , wherein R c is selected from lower alkyl, aryl or -loweralkyl-aryl; or -lower alkyl-OR d , wherein R d is a suitable protecting group;
all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents.