Modular synthesis of aminoglycosides
The present disclosure relates to novel methods for preparing antibacterial aminoglycoside compounds and the compounds used in such preparations.
1. A process for preparing a compound of formula A-5,
A-5, or a salt thereof,
wherein:
R 1a and R 1b are independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 6 cycloalkyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR 12 , —SO 2 R 13 , —OSF 2 NR 14 R 15 , —NR 14 R 15 , —N 3 , and —OR 16 , and
wherein each R 12 , R 13 , R 14 , R 15 , and R 16 is independently H or alkyl; or
R 1a and R 1b , together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group or heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR 22 , —SO 2 R 23 , —NR 24 R 25 , and —OR 26 , and
wherein each R 22 , R 23 , R 24 , R 25 , and R 26 is independently H or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, NR 14 R 15 , and —OR 16 ;
R 2a , R 2b , R 3a and R 3b are independently selected from the group consisting of H, —OR 27 , —NR 28 R 29 , halogen, C 1 -C 4 cycloalkyl, and C 1 -C 6 alkyl, wherein each R 27 , R 28 , and R 29 is independently H, alkyl, amino protecting group, or hydroxyl protecting group; wherein the C 1 -C 6 alkyl or alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of aryl, halogen, —OR 30 , —NR 31 R 32 , —SR 33 , and —SO 2 R 34 ;
wherein each R 30 , R 31 , R 32 , R 33 , and R 34 is independently H or alkyl substituted with one or more substituents independently selected from the group consisting of halogen, cyano, NR 14 R 15 , and —OR 16 ; or
R 2a and R 2b form an oxo or imino group substituted with C 1 -C 6 alkyl;
R 3a and R 3b form an oxo or imino group substituted with C 1 -C 6 alkyl;
X 1 is —F, —Cl, —Br, or —I;
LVG 1 is a leaving group;
N 1a is —NHPg 1a , —N(Pg 1a ) 2 , or N 3 , wherein each Pg 1a is independently an amino protecting group;
m is zero, 1, or 2;
n is zero, 1, or 2; and,
wherein m+n is 1, 2 or 3;
the process comprising:
(a) contacting a compound of formula A-1:
or a salt thereof, with a chiral auxiliary reagent to yield a compound of formula A-2:
or a salt thereof, wherein Xc is a chiral auxiliary group;
(b) contacting the compound of formula A-2 with a Grignard or organolithium reagent to yield a compound of formula A-3:
or a salt thereof;
(c) contacting the compound of formula A-3 with a halogen reagent in presence of a nucleophile reagent (Nuc-1) to yield a compound of formula A-4:
or a salt thereof,
wherein:
X 1 is —F, —Cl, —Br, or —I;
Nuc-1 is LVG 1 -M, wherein M is H, a metal cation, a non-metal cation, or a lone pair of electrons;
LVG 1 is a leaving group; and
(d) exchanging the chiral auxiliary group for an amino protecting group in the compound of formula A-4 by reaction with an amino protecting group reagent to yield the compound of formula A-5.
2. The process of claim 1 , further comprising after step (d):
(e) converting X 1 in the compound of formula A-5 to X to yield a compound of formula A-6:
or a salt thereof, wherein X is —NH 2 , —N 3 , a protected amino group, —OH, or a protected hydroxyl group.
3. A process for preparing a compound of formula A-5a,
A-5a, or a salt thereof,
wherein:
R 1a and R 1b are independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 6 cycloalkyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR 12 , —SO 2 R 13 , —OSF 2 NR 14 R 15 , —NR 14 R 15 , —N 3 , and —OR 16 , and
wherein each R 12 , R 13 , R 14 , R 15 , and R 16 is independently H or alkyl; or
R 1a and R 1b , together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group or heterocycloalkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, aryl, heteroaryl, —SR 22 , —SO 2 R 23 , —NR 24 R 25 , and —OR 26 , and
wherein each R 22 , R 23 , R 24 , R 25 , and R 26 is independently H or alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, cyano, NR 14 R 15 , and —OR 16 ;
R 2a , R 2b , and R 3a are independently selected from the group consisting of H, —OR 27 , —NR 28 R 29 , halogen, C 1 -C 4 cycloalkyl, and C 1 -C 6 alkyl, wherein each R 27 , R 28 , and R 29 is independently H or alkyl; wherein the C 1 -C 6 alkyl or alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of aryl, halogen, —OR 30 , —NR 31 R 32 , —SR 33 , and —SO 2 R 34 ;
wherein each R 30 , R 31 , R 32 , R 33 , and R 34 is independently H or alkyl substituted with one or more substituents independently selected from the group consisting of halogen, cyano, NR 14 R 15 , and —OR 16 ; or
R 2a and R 2b form an oxo or imino group substituted with C 1 -C 6 alkyl;
R 3b is H;
N 1b is —NHPg 1b , —N(Pg 1b ) 2 , or N 3 , wherein Pg 1b is an amino protecting group;
X 2 is —F, —Cl, —Br, or —I;
LVG 2 is a leaving group;
m is zero, 1, or 2;
n is zero, 1, or 2;
wherein m+n is 1, 2 or 3;
the process comprising:
(a) converting —OH in a compound of formula A-7
or a salt thereof, to R 3a to yield a compound of formula A-8:
or a salt thereof, and
(b) contacting the compound of formula A-8 with a halogen reagent in the presence of a nucleophile reagent (Nuc-2) to yield the compound of formula A-5a, wherein Nuc-2 is LVG 2 -M, wherein M is H, a metal cation, a non-metal cation, or a lone pair of electrons.
4. The process of claim 3 , further comprising after step (b):
(c) converting X 2 in the compound of formula A-5a to X to yield a compound of formula A-6a:
or a salt thereof, wherein X is —NH 2 , —N 3 , a protected amino group, —OH, or a protected hydroxyl group.