C3′-methylene hydrogen phosphonate oligomers and related compounds

A method of preparing an oligomer of formula II:

• wherein:
• Bx is a protected or unprotected heterocyclic base moiety;
• T1 is an oligonucleotide, oligonucleoside, nucleoside, nucleotide, H or a hydroxyl protecting group;
• each X1, X2 and X3 is, independently, O, S or NH;
• L is C(Y1)(Y2) or O, provided that at least one L is C(Y1)(Y2);
• R1 is Z0—(C2-C20 alkynyl);
• or R1 has one of formulas XI or XII:
• wherein:
• Z0 is O, S or NH;
• E is C1-C10 alkyl, N(Q1)(Q2) or N═C(Q1)(Q2);
• each Q1, and Q2 is, independently, H, C1-C10 alkyl, substituted alkyl, dialkylaminoalkyl, a nitrogen protecting group, a tethered or untethered conjugate group, a linker to a sold support;
• or Q1 and Q2, together, are joined in a nitrogen protecting group or a ring structure that can include at least one additional heteroatom selected from N and O;
• q1 is from 1 to 10;
• q2 is from 1 to 10;
• q3 is zero or 1;
• q4 is zero, 1 or 2;
• q5 is 1 to 10;
• each M1 is, independently, H, C1-C8 alkyl, C1-C8 haloalkyl, C(═NH)N(H)M2, C(═O)N(H)M2 or OC(═O)N(H)M2;
• M2 is H or C1-C8 alkyl;
• Z1, Z2 and Z3 comprise a ring system having from about 4 to about 7 carbon atoms or having from about 3 to about 6 carbon atoms and 1 or 2 heteroatoms wherein said heteroatoms are selected from oxygen, nitrogen and sulfur and wherein said ring system is aliphatic, unsaturated aliphatic, aromatic, or saturated or unsaturated heterocyclic;
• and
• Z4 is OM1, SM1, or N(M1)2;
• Z5 is alkyl or haloalkyl having 1 to about 10 carbon atoms, alkenyl having 2 to about 10 carbon atoms, alkynyl having 2 to about 10 carbon atoms, aryl having 6 to about 14 carbon atoms, N(Q1)(Q2), OQ1, halo, SQ1 or CN;
• m is 0 or 1;
• p is 0 or an integer from 1 to 50;
• and
• each of Y1 and Y2 is, independently, H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, cyano, carboxyl, ester or a cyclic moiety;
• comprising the steps of:
• (a) providing a 5′-protected nucleoside attached to a solid support;
• (b) cleaving the 5′-protecting group in the presence of an acid solution to form a 5′-deprotected nucleoside;
• (c) coupling said 5′-deprotected nucleoside with a monomer of formula I:
• wherein:
• Z6 is OH, OCH2CH2CN, N(i-Pr)2, dialkylamino, disubstituted alkylamino or O−HBy+;
• and
• By is an organic base moiety;
• in the presence of an condensing reagent to form a compound having an H-phosphonate linkage;
• (d) optionally capping said 5′-deprotected nucleoside with isopropylphosphite and pivaloyl chloride in acetonitrile and pyridine;
• (e) repeating steps (b) to (d) to form an oligomer of desired length and sequence;
• (f) oxidizing said H-phosphonate linkage with an oxidizing reagent to form an oxidized methylenephosphonate linkage;
• (g) repeating steps (b) to (f) to form an oligomer of desired length and sequence;
• and
• (h) cleaving said oligomer with aqueous ammonia.