Phosphine‐Free Stille–Migita Chemistry for the Mild and Orthogonal Modification of DNA and RNA

Abstract

An optimized catalyst system of [Pd2 (dba)3 ] and AsPh3 efficiently catalyzes the Stille reaction between a diverse set of functionalized stannanes and halogenated mono-, di- and oligonucleotides. The methodology allows for the facile conjugation of short and long nucleic acid molecules with moieties that are not compatible with conventional chemical or enzymatic synthesis, among them acid-, base-, or fluoride-labile protecting groups, fluorogenic and synthetically challenging moieties with good to near-quantitative yields. Notably, even azides can be directly introduced into oligonucleotides and (deoxy)nucleoside triphosphates, thereby giving direct access to "clickable" nucleic acids.

Palladium‐Mediated Labeling of Nucleic Acids

“…It was also noted that this chemistry could be applied to functionalize (deoxy)nucleoside triphosphates,adelicate class of compounds that can rapidly decompose outside an arrow and stringent range of conditions. [29,30] The mildnesso ft his methodology and its tolerance towards mostf unctional groups make this coupling reactionv ery attractive for the synthesis of complex oligonucleotides. Nevertheless, it should be kept in mind that workingw ith triorganotin-as well as triorganoarsenic-compounds requires full respect for good laboratory practices, due to their toxicity.…”

Fluorescent nucleobases as tools for studying DNA and RNA

“…A more reactive 5-iodothymine has also been explored that could undergo the coupling reaction at lower temperatures 97 . For Stille coupling, both 5-iodothymine and 2-iodoadenine have been explored to react with high excess of organostannane under the catalysis of palladium(0) triarylphosphine, heated to 60 °C in dimethylformamide 98,99 . In these examples, the fluorescent extensions are directly conjugated to the nucleobases.…”

Efficient Buchwald–Hartwig–Migita Cross‐Coupling for DNA Thioglycoconjugation

“…The first post‐functionalization was reported by Manderville who described Suzuki–Miyaura cross‐coupling reaction at C‐8 position of a guanine nucleobase from an oligonucleotide containing a single 8‐bromo‐2′‐deoxyguanosine residue (Scheme ) . An extentsion to Stille coupling reaction was then achieved by Jäschke who reported the efficient reaction of triorganotin compounds with iodine‐functionalized oligonucleotides and nucleotide triphosphates . Challenging substrates like hindered boronic acids have been incorporated by Suzuki–Miyaura cross‐coupling reaction for designing photo‐switchable nucleotides inside a duplex DNA .…”

“…[15] An extentsion to Stille coupling reaction was then achievedb yJ äschke who reported the efficient reaction of triorganotin compounds with iodine-functionalized oligonucleotides and nucleotide triphosphates. [16] Challenging substratesl ike hindered boronic acids have been incorporated by Suzuki-Miyaura cross-couplingr eactionf or designing photoswitchable nucleotides insideaduplex DNA. [17] Interestingly, sensitivea nd useful functional groupsw ere successfully incorporated by Davis using Suzuki-Miyaura cross-couplingr eaction to 5-iodouridine under mild conditions.…”