Synthesis of oligonucleotides and related compounds

A method of selectively conjugating an oligomer having protected nucleobases at its 3′-position, wherein the oligomer having protected nucleobases is represented by Formula (I-A) or (II A),

• or a salt thereof, wherein
• X is selected from the group consisting of —O—, —S—, —NR″—, and —C(R′)2—;
• B is a protected natural or unnatural nucleobase;
• R1 is selected from the group consisting of —OPG, F, —OR″, and —O(CR′2)1-2OCR′3;
• R1′ is selected from the group consisting of H, —OPG, F, —OR″, and —O(CR′2)1-2OCR′3;
• R2 is an oligonucleotide that is protected at the 5′-position, the oligonucleotide comprising protected natural or unnatural nucleobases;
• R3 is selected from the group consisting of H, —OPG, F, and —OR″, or R1 and R3 together form an optionally substituted 2-4 atom bridge;
• each R′ is independently selected from the group consisting of H, F, aryl, a C1-12alkyl, and a C1-12haloalkyl;
• each R″ is independently selected from the group consisting of H, aryl, a C1-12alkyl, and a C1-12haloalkyl;
• each PG is independently selected from the group consisting of 2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether (MEM), 2-naphthylmethyl ether (Nap), 4-methoxybenzyl ether (PMB), acetate (Ac), benzoate (Bz), benzyl ether (Bn), benzyloxymethyl acetal (BOM), methoxymethyl acetal (MOM), methoxypropyl acetal (MOP), methyl ether, and tetrahydropyranyl acetal (THP);
• L is C1-4alkyl;
• the dashed curve
• represents an aryl moiety;
• and
• R is a support moiety attached through one or more linkers to the aryl moiety, the method comprising the steps of:
• (a) reacting the oligomer having protected nucleobases represented by Formula (I-A) with a phosphine reagent to form a compound of Formula (III)
• wherein B is a protected natural or unnatural nucleobase, and wherein Y′ is —OH, and
• (b) reacting Y′ of Formula (III) with a monomer or a second oligomer to form a covalent bond between the 3′-position of Formula (III) and the monomer or second oligomer, thereby selectively conjugating the oligomer having protected nucleobases represented by Formula (I-A) at its 3′-position.

A compound of one of the following formulae:

• wherein
• Nuc is an oligonucleotide subunit having 1 to 30 linked nucleosides;
• B is a protected natural or unnatural nucleobase;
• X is absent, O or S;
• R1 is selected from the group consisting of —OPG, F, —OR″, and —O(CR′2)1-2OCR′3;
• R2 is PG;
• R3 is selected from the group consisting of H, —OPG, F, and —OR″, or R1 and R3 together form an optionally substituted 2 to 4 atom bridge;
• each R′ is independently selected from the group consisting of H, F, aryl, a C1-12alkyl, and a C1-12haloalkyl;
• each R″ is independently selected from the group consisting of H, aryl, a C1-12alkyl, and a C1-12haloalkyl;
• each PG is independently selected from the group consisting of 2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether (MEM), 2-naphthylmethyl ether (Nap), 4-methoxybenzyl ether (PMB), acetate (Ac), benzoate (Bz), benzyl ether (Bn), benzyloxymethyl acetal (BOM), methoxymethyl acetal (MOM), methoxypropyl acetal (MOP), methyl ether, and tetrahydropyranyl acetal (THP);
• R6 is selected from the group consisting of a counterion, methyl, and 2-cyanoethyl;
• and
• R is a solid support or a soluble support moiety attached through one or more linkers.