Processes for the synthesis of oligomeric compounds

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The present invention provides methods for the preparation of oligomeric compounds having at least one phosphodiester or phosphorothioate internucleoside linkage.
Oligomeric compounds of the invention are prepared using a novel deprotection step to form phosphodiester or phosphorothioate internucleoside linkages.
The methods utilize an O-allyl phosphorus protecting group on one or all of the internucleoside linkages prior to the deprotection step.
This allyl protecting group is cleaved in a deblocking step using an aqueous solution of concentrated ammonium hydroxide having a thiol compound present in the solution.
As used herein, the term "oligomeric compound" refers to compounds containing a plurality of nucleoside monomer subunits that are joined by internucleoside linkages.
Preferred internucleoside linkages include phosphorus-containing linkages, such as phosphite, phosphodiester, phosphorothioate, and/or phosphorodithioate linkages.
The term "oligomeric compound," therefore, includes naturally-occurring oligonucleotides, their analogs, and synthetic oligonucleotides.
The methods of the present invention are useful for the preparation of oligomeric compounds containing monomeric subunits that are joined by a variety of linkages.
In a preferred embodiment of the invention oligomers are synthesized such that all internucleoside linkages bear an allyl protecting group that is amenable to deblocking in a single step with concentrated ammonium hydroxide having a mercapto compound present in the solution.
In some preferred embodiments, a first monomer attached to a solid support is elongated using P--O-allyl monomers or a mixture of P--O-allyl phosphoramidite monomers and other monomers such as .
beta.
-cyanoethyl phosphoramidite monomers.
The methods of the present invention have been used with automated DNA synthesizers to synthesize oligomeric compounds of desired length and sequence.
Some oligomeric compounds have been synthesized using only P--O-allyl phosphoramidite monomers