Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof

A method of synthesizing a compound of the formula:

• or salt thereof, comprising reacting a compound of the formula:
• or a salt thereof, with a compound of Formula (X):
• or a salt thereof, wherein:
• RX is unsubstituted alkyl, —Si(RS)3, —Sn(RS)3, substituted or unsubstituted benzyl, or MX;
• RY is unsubstituted alkyl, —Si(RS)3, —Sn(RS)3, substituted or unsubstituted benzyl, hydrogen, or MY;
• each RS is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• MX is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium;
• MY is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium;
• one of RU and RV is hydrogen, and the other one of RU and RV is an oxygen protecting group or —Si(RS)3;
• or
• RU and RV are each attached to the same
• to form a ring;
• each RS is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R4 is absent when is a double bond or is R or halogen;
• each is independently a single bond or a double bond, as valency permits;
• each R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
• each R is independently hydrogen, -L2-RH-L3-D, or an optionally substituted group selected from C1-20 alkyl, C1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or:
• two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R2 is independently R, —[C(R)2]q—OR, —[C(R)2]q—N(R)2, —[C(R)2]q—SR, —[C(R)2]q—OSi(R)3, —[C(R)2]q—OC(O)R, —[C(R)2]q—OC(O)OR, —[C(R)2]q—OC(O)N(R)2, —[C(R)2]q—OC(O)N(R)—S(═O)2R, or —[C(R)2]q—OP(OR)2;
• or
• R1 and R2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• each q is independently 0, 1, 2, 3, or 4;
• each R3 is independently —S(O)2R, —S(O)2—[C(R)2]q—R, —S(O)2—[C(R)2]q—B(OR)2, —S(O)2—[C(R)2]q—Si(R)3, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —P(O)(R)2, —P(O)(OR)2, or —P(O)[N(R)2]2:
• at least one instance of R1, R3, and R4 comprises R wherein R is -L2-RH-L3-D:
• each L2 is independently substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, or C2-20 heteroalkynylene, wherein:
• optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and C2-20 heteroalkynylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• and
• optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and substituted or unsubstituted, C2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• each RH is independently substituted or unsubstituted triazolylene, —O—, —S—, —NRA—, —C(═)O—, —C(═NRA)O—, —S(═O)O—, —S(═O)2O—, —C(═O)NRA—, —C(═NRA)NRA—, —S(═O)NRA—, —S(═O)2NRA—, —OC(═O)—, —OC(═NRA)—, —OS(═O)—, —OS(═O)2—, —NR AC(═)—, —NRAC(═NRA)—, —NRAS(═O)—, —NRAS(═O)2—, —OC(═O)O—, —OC(═NRA)O—, OS(O)O—, —OS(═O)2O—, —NRAC(═O)O—, —NRAC(═NRA)O—, —NRAS(═O)O—, —NRAS(═O)2O—, —OC(═O)NRA—, —OC(═NRA)NRA—, —OS(═O)NRA—, —OS(═O)2NRA—, —NRAC(═O)NRA—, —NRAC(═NRA)NRA—, —NRAS(═O)NRA—, —NRAS(═O)2NRA—, —C(═O)—, —C(═NRA)—, S(═O)—, —S(═O)2—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• each RA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
• each L3 is independently substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, or C2-20 heteroalkynylene, wherein:
• optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and C2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• and
• optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and substituted or unsubstituted, C2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• each D is independently absent, polymeric moiety, dendrimeric moiety, antibody, particle, bead, nanostructure, liposome, micelle, or vesicle;
• each RS is absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, or —OSi(R)3;
• or
• R6 and R6′ are taken together to form ═O, ═C(R)2 or ═NR;
• each n is independently 0, 1, 2, 3, or 4;
• and
• each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —P(R)2, —P(OR)2, —P(O)(R)2, —P(O)(OR)2, —P(O)[N(R)2]2, —B(R)2, —B(OR)2, or —Si(R)3;
• or:
• two R7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

A method of synthesizing a compound of the formula:

• or salt thereof, comprising reacting a compound of the formula:
• or salt thereof, with tritylhydrodisulfane, wherein:
• each R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
• each R is independently hydrogen, -L2-RH-L3-D, or an optionally substituted group selected from C1-20 alkyl, C1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or:
• two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R2 is independently R, —[C(R)2]q—OR, —[C(R)2]q—N(R)2, —[C(R)2]q—SR, —[C(R)2]—OSi(R)3, —[C(R)2]q—OC(O)R, —[C(R)2]q—OC(O)OR, —[C(R)2]q—OC(O)N(R)2, —[C(R)2]q—OC(O)N(R)—S(═O)2R, or —[C(R)2]q—OP(OR)2;
• or
• R1 and R2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• each q is independently 0, 1, 2, 3, or 4;
• each R3 is independently —S(O)2R, —S(O)2—[C(R)2]q—R, —S(O)2—[C(R)2]q—B(OR)2, —S(O)2—[C(R)2]q—Si(R)3, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —P(O)(R)2, —P(O)(OR)2, or —P(O)[N(R)2]2:
• at least one instance of R1 and R3 comprises R wherein R is -L2-RH-L3-D;
• each L2 is independently substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, or C2-20 heteroalkynylene, wherein:
• optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and C2-20 heteroalkynylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• and
• optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and substituted or unsubstituted, C2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• each RH is independently substituted or unsubstituted triazolylene, —O—, —S—, —NRA—, —C(O)O—, —C(═NRA)O—, —S(═O)O—, —S(═O)2O—, —C(═O)NRA—, —C(═NRA)NRA—, —S(═O)NRA—, —S(═O)2NRA—, —OC(═O)—, —OC(═NRA)—, —OS(═O)—, —OS(═O)2—, —NR AC(O), —NRAC(═NRA)—, —NRAS(═O)—, —NRAS(═O)2—, —OC(═O)O—, —OC(═NRA)O—, OS(O)O—, —OS(═O)2O—, —NRAC(═O)O—, —NRAC(═NRA)O—, —NRAS(═O)O—, —NRAS(O)2O—, —OC(═O)NRA—, —OC(═NRA)NRA—, —OS(═O)NRA—, —OS(═O)2NRA—, —NRAC(═O)NRA—, —NRAC(═NRA)NRA—, —NRAS(═O)NRA—, —NRAS(═O)2NRA—, —C(═O)—, —C(═NRA)—, S(O)—, —S(═O)2—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• each RA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
• each L3 is independently substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, or C2-20 heteroalkynylene, wherein:
• optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and C2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• and
• optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and substituted or unsubstituted, C2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• each D is independently absent, polymeric moiety, dendrimeric moiety, antibody, particle, bead, nanostructure, liposome, micelle, or vesicle;
• each R5 is absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, or —OSi(R)3;
• or
• R6 and R6′ are taken together to form ═O, ═C(R)2 or ═NR;
• each n is independently 0, 1, 2, 3, or 4;
• each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —P(R)2, —P(OR)2, —P(O)(R)2, —P(O)(OR)2, —P(O)[N(R)2]2, —B(R)2, —B(OR)2, or —Si(R)3;
• or:
• two R7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and
• each RS is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

A method of synthesizing a compound of the formula:

• or salt thereof, comprising reacting a compound of the formula:
• or a salt thereof, with a compound of Formula (X):
• or a salt thereof, wherein:
• RX is unsubstituted alkyl, —Si(RS)3, —Sn(RS)3, substituted or unsubstituted benzyl, or MX;
• RY is unsubstituted alkyl, —Si(RS)3, —Sn(RS)3, substituted or unsubstituted benzyl, hydrogen, or MY;
• each RS is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• MX is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium;
• MY is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium;
• one of RU and RV is hydrogen, and the other one of RU and RV is an oxygen protecting group or —Si(RS)3;
• or
• RU and RV are each attached to the same
• to form a ring;
• each RS is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R4 is absent when is a double bond or is R or halogen;
• each is independently a single bond or a double bond, as valency permits;
• each R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
• each R is independently hydrogen, -L2-RH1, or an optionally substituted group selected from C1-20 alkyl, C1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or:
• two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R2 is independently R, —[C(R)2]q—OR, —[C(R)2]q—N(R)2, —[C(R)2]q—SR, —[C(R)2]q—OSi(R)3, —[C(R)2]q—OC(O)R, —[C(R)2]q—OC(O)OR, —[C(R)2]q—OC(O)N(R)2, —[C(R)2]qOC(O)N(R)—S(═O)2R or —[C(R)2]q—OP(OR)2;
• or
• R1 and R2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• each q is independently 0, 1, 2, 3, or 4;
• each R3 is independently —S(O)2R, —S(O)2—[C(R)2]q—R, —S(O)2—[C(R)2]q—B(OR)2, —S(O)2—[C(R)2]q—Si(R)3, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —P(O)(R)2, —P(O)(OR)2, or —P(O)[N(R)2]2;
• at least one instance of R1, R3, and R4 comprises R wherein R is -L2-RH1;
• each L2 is independently substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, or C2-20 heteroalkynylene, wherein:
• optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and C2-20 heteroalkynylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• and
• optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and substituted or unsubstituted, C2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• each RH1 is independently a first click-chemistry handle, a nucleophile, an electrophile, a leaving group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, —OH, —SH, —NHRA, —N3, —C(═O)OH, —C(═NRA)OH, —S(═O)OH, —S(═O)2OH, —C(═O)-(a leaving group), —C(═NRA)-a leaving group), —S(═O)-(a leaving group), or —S(═O)2-a leaving group), provided that each RH1 is not —OCH3 or —NRAC(═O)RA;
• each RA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
• each R5 is absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, or —OSi(R)3;
• or
• R6 and R6′ are taken together to form ═O, ═C(R)2 or ═NR;
• each n is independently 0, 1, 2, 3, or 4;
• and
• each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —P(R)2, —P(OR)2, —P(O)(R)2, —P(O)(OR)2, —P(O)[N(R)2]2, —B(R)2, —B(OR)2, or —Si(R)3;
• or:
• two R7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

A method of synthesizing a compound of the formula:

• or salt thereof, comprising reacting a compound of the formula:
• or salt thereof, with tritylhydrodisulfane, wherein:
• each R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
• each R is independently hydrogen, -L2-RH1, or an optionally substituted group selected from C1-20 alkyl, C1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or:
• two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R2 is independently R, —[C(R)2]q—OR, —[C(R)2]q—N(R)2, —[C(R)2]q—SR, —[C(R)2]q—OSi(R)3, —[C(R)2]q—OC(O)R, —[C(R)2]q—OC(O)OR, —[C(R)2]q—OC(O)N(R)2, —[C(R)2]qOC(O)N(R)—S(═O)2R or —[C(R)2]q—OP(OR)2;
• or
• R1 and R2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• each q is independently 0, 1, 2, 3, or 4;
• each R3 is independently —S(O)2R, —S(O)2—[C(R)2]q—R, —S(O)2—[C(R)2]q—B(OR)2, —S(O)2—[C(R)2]q—Si(R)3, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —P(O)(R)2, —P(O)(OR)2, or —P(O)[N(R)2]2;
• at least one instance of R1 and R3 comprises R wherein R is -L2-RH1;
• each L2 is independently substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, or C2-20 heteroalkynylene, wherein:
• optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C1-20 alkylene, substituted or unsubstituted, C2-20 alkenylene, substituted or unsubstituted, C2-20 alkynylene, substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and C2-20 heteroalkynylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• and
• optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C1-20 heteroalkylene, substituted or unsubstituted, C2-20 heteroalkenylene, and substituted or unsubstituted, C2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• each RH1 is independently a first click-chemistry handle, a nucleophile, an electrophile, a leaving group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, —OH, —SH, —NHRA, —N3, —C(═O)OH, —C(═NRA)OH, —S(═O)OH, —S(═O)2OH, —C(═O)-(a leaving group), —C(═NRA)-a leaving group), —S(═O)-(a leaving group), or —S(═O)2-a leaving group), provided that each RH1 is not —OCH3 or —NRAC(═O)RA;
• each RA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
• each R5 is absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, or —OSi(R)3;
• or
• R6 and R6′ are taken together to form ═O, ═C(R)2 or ═NR;
• each n is independently 0, 1, 2, 3, or 4;
• each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —P(R)2, —P(OR)2, —P(O)(R)2, —P(O)(OR)2, —P(O)[N(R)2]2, —B(R)2, —B(OR)2, or —Si(R)3;
• or:
• two R7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and
• each RS is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

A method of synthesizing a compound of the formula:

• or salt thereof, comprising reacting a compound of the formula:
• or a salt thereof, with a compound of Formula (X):
• or a salt thereof, wherein:
• RX is unsubstituted alkyl, —Si(RS)3, —Sn(RS)3, substituted or unsubstituted benzyl, or MX;
• RY is unsubstituted alkyl, —Si(RS)3, —Sn(RS)3, substituted or unsubstituted benzyl, hydrogen, or MY;
• each RS is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• MX is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium;
• MY is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium;
• one of RU and RV is hydrogen, and the other one of RU and RV is an oxygen protecting group or —Si(RS)3;
• or
• RU and RV are each attached to the same
• to form a ring;
• each RS is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R4 is absent when is a double bond or is R or halogen;
• each is independently a single bond or a double bond, as valency permits;
• each R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
• each R is independently hydrogen or an optionally substituted group selected from C1-20 alkyl, C1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or:
• two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R2 is independently R, —[C(R)2]q—OR, —[C(R)2]q—N(R)2, —[C(R)2]q—SR, —[C(R)2]q—OSi(R)3, —[C(R)2]q—OC(O)R, —[C(R)2]q—OC(O)OR, —[C(R)2]q—OC(O)N(R)2, —[C(R)2]qOC(O)N(R)—S(═O)2R, or —[C(R)2]q—OP(OR)2;
• or
• R1 and R2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• each q is independently 0, 1, 2, 3, or 4;
• each R3 is independently —S(O)2R, —S(O)2—[C(R)2]q—R, —S(O)2—[C(R)2]q—B(OR)2, —S(O)2—[C(R)2]q—Si(R)3, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —P(O)(R)2, —P(O)(OR)2, or —P(O)[N(R)2]2;
• each R5 is absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, or —OSi(R)3;
• or
• R6 and R6′ are taken together to form ═O, ═C(R)2, or ═NR;
• each n is independently 0, 1, 2, 3, or 4;
• and
• each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —P(R)2, —P(OR)2, —P(O)(R)2, —P(O)(OR)2, —P(O)[N(R)2]2, —B(R)2, —B(OR)2, or —Si(R)3;
• or:
• two R7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

A method of synthesizing a compound of the formula:

• or salt thereof, comprising reacting a compound of the formula:
• or salt thereof, with tritylhydrodisulfane, wherein:
• each R1 is independently R, —C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, —S(O)2OR, —C(R)2OR, or —S(O)2N(R)2;
• each R is independently hydrogen or an optionally substituted group selected from C1-20 alkyl, C1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or:
• two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R2 is independently R, —[C(R)2]q—OR, —[C(R)2]q—N(R)2, —[C(R)2]q—SR, —[C(R)2]q—OSi(R)3, —[C(R)2]q—OC(O)R, —[C(R)2]q—OC(O)OR, —[C(R)2]q—OC(O)N(R)2, —[C(R)2]qOC(O)N(R)—S(═O)2R, or —[C(R)2]q—OP(OR)2;
• or
• R1 and R2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• each q is independently 0, 1, 2, 3, or 4;
• each R3 is independently —S(O)2R, —S(O)2—[C(R)2]q—R, —S(O)2—[C(R)2]q—B(OR)2, —S(O)2—[C(R)2]q—Si(R)3, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —P(O)(R)2, —P(O)(OR)2, or —P(O)[N(R)2]2;
• each R5 is absent when is a double bond or is independently hydrogen or an optionally substituted C1-6 aliphatic group;
• each of R6 and R6′ is independently R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, or —OSi(R)3;
• or
• R6 and R6′ are taken together to form ═O, ═C(R)2, or ═NR;
• each n is independently 0, 1, 2, 3, or 4;
• each R7 is independently R, halogen, —CN, —NO2, —OR, —OSi(R)3, —SR, —N(R)2, —S(O)2R, —S(O)2OR, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R)2, —N(R)S(O)2R, —P(R)2, —P(OR)2, —P(O)(R)2, —P(O)(OR)2, —P(O)[N(R)2]2, —B(R)2, —B(OR)2, or —Si(R)3;
• or:
• two R7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and
• each RS is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.