Pergamon TETRAHEDRON LETTERS Tetrahedron Letters 39 (1998) 1299-l 302 Divergent Solid-Phase Synthesis of Nucleic Acid Dendrimers Robert H.E. Hudson?’ Sebastien Robidoux, and Masad J. Damha* Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montreal, QC, Canada H3A 2K6 ‘Department of Chemistry, Erindale College, U. of Toronto, Mississauga, ON Canada, L~L lC6 Received 19 November 1997; accepted 8 December 1997 Abstract: A divergent or “starburst” approach for the construction of branched nucleic acids mimicking naturally occuring lariat and forked introns is described. Chain assembly takes place on the surface of controlled-pore glass solid support in the unconventional 5’ to 3’ direction. The branch junctures were introduced by use of N6-benzoyl-2’,3’-0-bis(dimethoxytrityl)adenosine-5’-O-(N,N-diisopropyl)-~- cyanoethylphosphoramidite. Various dendrimers were prepared in comparable or better yields relative to the convergent approach. 0 1998 Elsevier Science Ltd. All rights reserved. The groups of Tomalia, Newkome and Frechet have vitalized the area of synthetic macromolecular science concerned with highly branched molecules known as “dendrimers”.*’ The general approach employed by Tomalia and others, especially Newkome,3 is a divergent or cascade-type reaction in which geometric growth is achieved. Chiral dendrimers based on biotic monomers, in particular lysine, have been reported by Denkewalter and others.5,6 A divergent branching scheme has been employed by Chiron to produce nucleic acids containing multiple-fork networks,‘,‘or “comb”-like structures.’ The latter structures, termed “multimers” by Horn and Urdea, have found use as nucleic acid probes in biochemical (diagnostic) assays.’ Sometime ago, our group described the use of nucleoside branching monomers, particularly adenosine, for the convergent synthesis of branched nucleic acids containing vicinal 2’,5’- and 3’,5’-phosphodiester linkages (“bNAs”, Scheme 1 ).‘.” The architecture of these molecules is reminiscent of “lariat” RNA and multi-copy single stranded DNA (msDNA), which are unusual and important structures relevant to mRNA splicing.““* Scheme 1 CONVERGENT GROWTH ref. 9,io k 3*&m-s- BRANCHING TT15 CLEAVAGE \* ‘l/“-shape dendron s’d-TTTTTTTm-5’ 2’P 3*&A -II DEPROTECTION /$ m5 IA1 In consideration of the potential value of bNAs for investigating biological phenomenal3 and nucleic acid structure,‘4.‘5 and also the practical limitations encountered in our convergent synthesis of dendritic bNAs,‘O a divergent synthetic strategy has been designed (Scheme 2). Our divergent approach requires the chemical synthesis to take place in the 5’ -+ 3’ (“backward”) direction rather than the conventional 3’ + 5’ direction. Like the convergent approach, the assembly of oligonucleotides is done on the surface of long-chain alkylamine controlled-pore glass (LCAA-CPG) with an automated DNA synthesizer and employs two distinctive synthons. Specifically, chain elongation is achieved with a 5’-O-(N,N-diisopropyI)-P-cyanoethylphosphoramidite-~-O- dimethoxytrityl-2’-deoxynucleoside (I) and branch-points are introduced by use of a 0040-4039/98/$19.00 0 1998 Elsevier Science Ltd. All rights reserved. PII: SOO40-4039(97)10871-l