Modular synthesis of aminoglycosides

A process for preparing a compound of formula ABCD-1:

• or a salt thereof,
• wherein:
• R1a and R1b are independently selected from the group consisting of H, C1-C12 alkyl, C1-C6 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, —SR12, —SO2R13, —OSF2NR14R15, —NR14R15, —N3, and —OR16, and
• wherein each R12, R13, R14, R15 and R16 is independently H or alkyl;
• or
• R1a and R1b, 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, —SR22, —SO2R23, —NR24R25, and —OR26, and
• wherein each R22, R23, R24, R25, and R26 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, NR14R15 and —OR16;
• R2a, R2b, R3a and R3b are independently selected from the group consisting of H, —OR27, —NR28R29, halogen, C1-C4 cycloalkyl, and C1-C6 alkyl, wherein each R27, R28, and R29 is independently H, alkyl, amino protecting group, or hydroxyl protecting group;
• wherein the C1-C6 alkyl or alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of aryl, halogen, —OR30, —NR31R32, —SR33, and —SO2R34;
• wherein each R30, R31, R32, R33 and R34 is independently H or alkyl substituted with one or more substituents independently selected from the group consisting of halogen, cyano, NR14R15 and —OR16;
• or
• R2a and R2b form an oxo or imino group substituted with C1-C6 alkyl;
• R3a and R3b form an oxo or imino group substituted with C1-C6 alkyl;
• R4aa and R4bb are, independently H, —OH, —OR40, —NR41R42, or halogen;
• wherein each R40, R41, and R42 are independently H, alkyl, —CONH2, or —COCH3;
• wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, halogen, and substituted heteroaryl;
• R5aa is H, —CN, —CONH2 or C1-C3alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —OH, —OC(O)CH3, —NH2, —CN, —CONH2, and halogen;
• R6a and R6b are, independently H, halogen, NH2, —OH, C1-C3alkoxy, —OC(O)CH3, or -OPg2m;
• wherein Pg2m is a hydroxyl protecting group;
• N1s is N3 or —NR8aR8b;
• R8a is H, C1-C6 alkyl, an amino protecting group, or
• wherein
• Q1 is NH, O, or S;
• z is an integer from 0 to 4, 35z
• R35z is H or C1-C3 alkyl;
• H
• each R36z and R37z is independently selected from the group consisting of H, alkyl, halogen, and —OH, and
• R38z is H, alkyl, or —C(═NH)NR39zR40z wherein R39z and R40z are independently H or C1-C3 alkyl;
• or
• R35z and R38z, together with the atoms to which they are attached, form a heterocycloalkyl group comprising at least one N;
• R8b is H or C1-C3alkyl;
• N1e is —OH, protected hydroxyl group, —NHPg1e or N3, wherein Pg1e is an amino protecting group;
• N1f is —NHPg1f or N3, wherein Pg1f is an amino protecting group;
• X7 is H, —NH2, —N3, protected amino group, —OH, protected hydroxyl group, or halogen;
• m is zero, 1, or 2;
• n is zero, 1, or 2;
• wherein m+n is 1, 2 or 3;
• o is zero, 1, or 2;
• p is zero, 1, or 2;
• wherein o+p is 1, 2 or 3;
• R7a, R7b, and R7c are independently H, NH2, OH, —OR71 or -OPg2r;
• wherein R71 is alkyl;
• wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, halogen, and substituted heteroaryl;
• wherein Pg2r is a hydroxyl protecting group;
• R9a and R9b are independently H, OH, or —OR91,
• wherein R91 is alkyl, alkenyl, or alkynyl;
• wherein the alkyl, alkenyl, and alkynyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R10a and R10b are independently H, OH, or —OR101,
• wherein R101 is alkyl, alkenyl, or alkynyl;
• wherein the alkyl, alkenyl, and alkynyl is unsubstituted or substituted with one or more substituents selected from the group consisting of —CONH2, —OH, —NH2, —COCH3, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• N1g is —NHPg1g or N3, wherein Pg1g is an amino protecting group;
• N1h is —NHPg1h or N3, wherein Pg1h is an amino protecting group;
• Pg2g is a hydroxyl protecting group;
• Pg2h is a hydroxyl protecting group;
• q is zero, 1, or 2;
• r is zero, 1, or 2;
• wherein q+r is 1, 2 or 3;
• the process comprising:
• (a) contacting a compound of formula A-9′:
• wherein LVG3 is a leaving group,
• with a compound of formula B-12:
• where Pg2e is a hydroxyl protecting group, to yield a compound of formula AB-1′:
• (b) selectively deprotecting the compound of formula AB-1′ by removing the Pg2e moiety to yield a compound of formula AB-3′:
• or a salt thereof;
• (c) contacting the compound of formula AB-3′ with a compound of formula CD-1,
• or a salt thereof, where LVG5 is a leaving group;
• to yield the compound of formula ABCD-1′, or a salt thereof.