Oligonucleotide compositions and methods of use thereof

A method for preparing an oligonucleotide, wherein the oligonucleotide comprises one or more phosphoramidate internucleotidic linkages, comprising providing a phosphoramidite compound having the structure of:

• or a salt thereof,
• wherein a base is contacted with an oligonucleotide having an internucleotidic linkage having the structure of formula III (the “formula III oligonucleotide”):
• wherein the contact is performed substantially absent of water and the contact is after the length of the oligonucleotide to be prepared is achieved before deprotection and cleavage of the formula III oligonucleotide;
• and
• wherein:
• PN is P(═N-L-R5),
• R5s is independently R′ or —OR′;
• each BA is independently an optionally substituted group selected from C3-30 cycloaliphatic, C6-30 aryl, C5-30 heteroaryl having 1-10 heteroatoms, C3-30 heterocyclyl having 1-10 heteroatoms, a natural nucleobase moiety, and a modified nucleobase moiety;
• each Rs is independently —H, halogen, —CN, —N3, —NO, —NO2, -L-R′, -L-Si(R)3, -L-OR′, -L-SR′, -L-N(R′)2, —O-L-R′, —O-L-Si(R)3, —O-L-OR′, —O-L-SR′, or —O-L-N(R′)2;
• each s is independently 0-20;
• each L′ is independently —C(R5s)2—, or L;
• Q− is an anion;
• Lb is L or —N(R1)—;
• g is 0-18;
• each of X, Y and Z is independently —O—, —S—, —N(-L-R5)—, or L;
• each L is independently a covalent bond, or a bivalent, optionally substituted, linear or branched group selected from a C1-30 aliphatic group and a C1-30 heteroaliphatic group having 1-10 heteroatoms, wherein one or more methylene units are optionally and independently replaced with C1-6 alkylene, C1-6 alkenylene, —C≡C—, a bivalent C1-C6 heteroaliphatic group having 1-5 heteroatoms, —C(R′)2—, —Cy—, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, C(O)S—, —C(O)O—, —P(O)(OR′)—, —P(O)(SR′)—, —P(O)(R′)—, —P(O)(NR′)—, —P(S)(OR′)—, —P(S)(SR′)—, —P(S)(R′)—, —P(S)(NR′)—, —P(R′)—, —P(OR′)—, —P(SR′)—, —P(NR′)—, —P(OR′)[B(R′)3]—, —OP(O)(OR′)O—, —OP(O)(SR′)O—, —OP(O)(R′)O—, —OP(O)(NR′)O—, —OP(OR′)O—, —OP(SR′)O—, —OP(NR′)O—, —OP(R′)O—, or —OP(OR′)[B(R′)3]O—, and one or more CH or carbon atoms are optionally and independently replaced with CyL;
• each —Cy— is independently an optionally substituted bivalent group selected from a C3-20 cycloaliphatic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms;
• each CyL is independently an optionally substituted trivalent or tetravalent group selected from a C3-20 cycloaliphatic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms;
• each Ring A is independently an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;
• Ring AL is an optionally substituted 3-20 monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to the two depicted nitrogen atoms;
• each of G1, G2, G3, G4, and G5is independently R1;
• each of R1 and R5 is independently —H, -L-R′, halogen, —CN, —NO2, -L-Si(R′)3, —OR′, —SR′, or —N(R′)2;
• each R′ is independently —R, —C(O)R, —C(O)OR, or —S(O)2R;
• each R is independently —H, or an optionally substituted group selected from C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms, C6-30 aryl, C6-30 arylaliphatic, C6-30 arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1-10 heteroatoms, or
• two R groups are optionally and independently taken together to form a covalent bond, or
• two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms, or
• two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms;
• —X-L-R1 is
• and
• wherein G2 comprises an electron-withdrawing group.