Synthesis of morpholino oligomers using doubly protected guanine morpholino subunits

A method of synthesizing a morpholino oligomer, the method comprising:

• (a) reacting
• a solid-phase-supported morpholino subunit monomer comprising an unprotected morpholino ring nitrogen
• with a first morpholino subunit monomer comprising a triarylmethyl-protected morpholino ring nitrogen and an activated phosphoramidate group on a 5′-exocyclic carbon, thereby forming a phosphorodiamidate linkage between the 5′-exocyclic carbon of the first morpholino subunit monomer and the unprotected morpholino ring nitrogen of the solid-phase-supported morpholino subunit monomer;
• (b) deprotecting the triarylmethyl-protected morpholino ring nitrogen to form a product comprising an unprotected morpholino ring nitrogen;
• (c) optionally reacting the product from step (b) with a further morpholino subunit monomer comprising a triarylmethyl-protected morpholino ring nitrogen and an activated phosphoramidate group on a 5′-exocyclic carbon, thereby forming a phosphorodiamidate linkage between the 5′-exocyclic carbon of the further morpholino subunit monomer and the unprotected morpholino ring nitrogen of the product from step (b);
• and
• (d) optionally repeating steps (b) and (c) one or more times;
• wherein at least one of the first morpholino subunit monomer, the further morpholino subunit monomer or the solid-phase-supported morpholino subunit monomer is a doubly protected guanine morpholino compound having the following structure I:
• wherein:
• R1 is lower alkyl, di(lower alkyl)amino or phenyl;
• R2 is lower alkyl, monocyclic arylmethyl or monocyclic (aryloxy)methyl;
• R3 is triarylmethyl or hydrogen;
• and
• Y is a chlorophosphoramidate group or a linkage to a solid support.