Oligonucleosides with a Nucleobase‐Including Backbone. Part 12

Abstract

In contradistinction to the corresponding Grignard reagent, bis[(trimethylsilyl)ethynyl]zinc reacted with the 5′‐oxoadenosine 3 diastereoselectively to the β‐D‐allo‐hept‐6‐ynofuranosyladenine 5. Lithiation/iodination of the monomeric propargyl alcohol 5 and of the dimeric propargyl alcohol 22 provided the 8‐iodoadenosines 7 and 18, respectively, considerably shortening the synthesis of the dimeric O‐silylated 8‐iodoadenosine 25. The mixed uridine‐ and adenosine‐derived tetramers 21 and 32 were synthesised. The tetramer 21 was prepared by a linear sequence. Sonogashira coupling of 9 and 13 yielded the trimer 16 that was C‐desilylated to 17. A second Sonogashira coupling of 17 and 19 yielded the tetramer 21. Tetramer 32 was prepared in higher yields by a convergent route, coupling the acetylene 29 and the iodide 30. The uridine‐derived iodides proved more reactive than the adenosine‐derived analogues, and the N6‐unprotected adenosine‐derived alkynes were more reactive than their N6‐benzoylated analogues.

Structural Basis of Duplex Thermodynamic Stability and Enhanced Nuclease Resistance of 5′-C-Methyl Pyrimidine-Modified Oligonucleotides

“…41,42 Here, we describe an improved organomagnesium procedure for the synthesis of a variety of 5′-C-methyl pyrimidine nucleosides with different 2′-substituents and simple silica gel column chromatography and crystallization techniques for complete separation of the stereoisomeric products (Scheme 1). Dess−Martin oxidation 33,52 of 3′-O-TBS-protected nucleosides 1a−d afforded unstable aldehydes 2a−d that tend to form hydrates, cyclic products, and oligomers 41,44,52,53 and also can potentially undergo epimerization at the 4′-position. 43 The aldehydes 2a−d constituted 60−70% of the crude mixtures as determined by 1 H NMR.…”

“…6 Thermal melting temperatures of the duplexes were determined as described in the literature. 53 SVPD Stability Measurements and Graphs. DNA single strand solutions were prepared at 0.1 mg/mL concentration in 50 mM TRIS-HCl buffer (pH 8), containing 10 mM MgCl 2 .…”

Oligonucleosides with Integrated Backbone and Base: Foldamers with a Novel Architecture

“…However, conformational analysis of the dimer 5 demonstrated a persistent hydrogen bond between the propargylic hydroxy group and N(3) of the same monomeric unit that is only compatible with a syn conformation [43]. In keeping with this observation, fully deprotected tetramers did not pair in MeOH, while the protected tetramer 6 associated in CDCl 3 [41] [44]. This suggested to either remove the propargylic hydroxy group, or to design new analogues that pair in a syn conformation.…”

“…3). An ethynylene-linked uridine-derived hexamer and an adenosine-derived tetramer were obtained by a linear and/or convergent approach, including oxidation of the C(5ʹ) hydroxymethyl to a formyl group, a diastereoselective addition of an ethynyl zinc or magnesium reagent, and Sonogashira coupling to a C(8) bromo or iodo nucleoside [40][41][42]. As a rule, C(8)-substituted purines and C(6)-substituted pyrimidines prefer the syn conformation, while the design of the oligomers 3 and 4, based upon the structure of B DNA, postulated an anti conformation of the nucleobases.…”

Novel nucleotide analogues bearing (1 H -1,2,3-triazol-4-yl)phosphonic acid moiety as inhibitors of Plasmodium and human 6-oxopurine phosphoribosyltransferases

“…5 trityl groups using methylamine in toluene 21 and 80% aq. acetic acid, respectively, followed by removal of phosphonate ethyl ester moieties with Me 3 SiBr/MeCN with ensuing hydrolysis, 22 afforded final products (R)-8 or (S)-8 (Scheme 1).…”