Macrolides and methods of their preparation and use

A compound of formula:

• or a salt thereof;
• wherein:
• Y2 is —Z4H, —CH2NO2, a leaving group (LG), —C(═O)RZ3, —C(═O)ORZ3, —C(═O)LG, —C(═O)—CH═P(RP1)(RP2)(RP3), or —C(═O)—CH2—P(O)(ORP2)(ORP3);
• Z4 is —O—, —S—, or —NRZ2—;
• RP1, RP2, and RP3 are each independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• L2 is a bond or —CH2—;
• z2 is 0, 1, or 2;
• each instance of R2a and R2b is independently hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or wherein R2a and R2b can be taken together to form
• RZ2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, amino, substituted amino, —C(═O)RZ8, —C(═O)ORZ8, —C(═O)N(RZ8)2, or a nitrogen protecting group;
• RZ3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• L3 is a group of formula:
• represents a single or double bond;
• R3 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)RZ8, —C(═O)ORZ8, —C(═O)N(RZ8)2, an oxygen protecting group, or a group of formula:
• R4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• each instance of R18 and R19 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• each instance of R20 and R21 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, halogen, or carbonyl, or R20 and R21 are joined to form an optionally substituted cyclopropyl or an oxiranyl ring;
• each instance of R5a and R5b is independently hydrogen, halogen, silyl, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
• R9 is optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)RZ8, —C(═O)ORZ8, —C(═O)N(RZ8)2, or a carbohydrate;
• G2 is a group of formula:
• R6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, silyl, or halogen;
• R10 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, silyl, or halogen;
• each instance of XG2 is —OR15, —SR15, or —N(R15)2;
• each instance of R15 is independently silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R15 groups can be taken together to form an optionally substituted heteroaryl or heterocyclic ring;
• each instance of R16a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• each instance of LC1 and LC2 is independently a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, or combinations thereof;
• each instance of A1 is independently a leaving group (LG), —SH, —OH, —NH2, —NH—NH2, —N3, —O—NH2, —C(═O)RX1,
• A is —NH—, —NH—NH—, —NH—O—, —O—NH—, —S—, —O—,
• optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—, or —O—;
• W is O, S, or NRW1;
• RW1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
• RW2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RW2 groups are joined to form an optionally substituted cyclic moiety;
• RX1 is hydrogen, halogen, or —ORX2, wherein RX2 is hydrogen, optionally substituted alkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
• R23 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• each instance of RZ8 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RZ8 groups are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring;
• and
• LG is a leaving group.