Using 1,3-dithian-2-yl-methoxycarbonyl (Dmoc) as protecting groups and linker for oligodeoxynucleotide (ODN) synthesis, deprotection and cleavage are achieved under non-nucleophilic oxidative conditions. The nucleophile-sensitive thioester and α-chloroacetyl groups are conveniently incorporated into ODN sequences. The technology could be universally useful for electrophilic ODN synthesis.
Solid-phase synthesis of electrophilic oligodeoxynucleotides (ODNs) was achieved using dimethyl-Dmoc (dM-Dmoc) as amino protecting group. Due to the high steric hindrance of the 2-(propan-2-ylidene)-1,3-dithiane side product from deprotection, the use of excess nucleophilic scavengers such as aniline to prevent Michael addition of the side product to the deprotected ODN during ODN cleavage and deprotection was no longer needed. The improved technology was demonstrated by the synthesis and characterization of five ODNs including three modified ones. The modified ODNs contained the electrophilic groups ethyl ester, α-chloroamide, and thioester. Using the technology, the sensitive groups can be installed at any location within the ODN sequences without using any sequence- or functionality-specific conditions and procedures.
Rh(III) -catalyzed N-nitroso-directed CH addition to ethyl 2-oxoacetate allows subsequent construction of indazoles, a privileged heterocycle scaffold in synthetic chemistry, through the exploitation of reactivity between the directing group and installed group. The formal [2+2] cycloaddition/fragmentation reaction pathway identified herein, a unique reactivity pattern hitherto elusive for the N-nitroso group, emphasizes the importance of forward reactivity analysis in the development of useful CH functionalization-based synthetic tools. The synthetic utility of the protocol is demonstrated with the synthesis of a tricyclic-fused ring system. The diversity of covalent linkages available for the nitroso group should enable the extension of the genre of reactivity reported herein to the synthesis of other types of heterocycles.
In traditional oligodeoxynucleotide
(ODN) synthesis, phosphate
groups are protected with the 2-cyanoethyl group, and amino groups
are protected with acyl groups. At the end of ODN synthesis, deprotection
is achieved with strong bases and nucleophiles. Therefore, traditional
technologies are not suitable for the synthesis of ODNs containing
sensitive functionalities. To address the problem, we report the use
of Dim and Dmoc groups, which are based on the 1,3-dithian-2-yl-methyl
function, for phosphate and amine protection for the solid phase ODN
synthesis. Using the new Dim–Dmoc protection, deprotection
was achieved under mild oxidative conditions without using any strong
bases and nucleophiles. As a result, the new technology is suitable
for the synthesis of ODNs containing sensitive functions. To demonstrate
feasibility, seven 20-mer ODNs including four that contain sensitive
ester and alkyl chloride groups were synthesized, purified with RP
HPLC, and characterized with MALDI-TOF MS and enzyme digestion essays.
High purity ODNs were obtained.
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