Synthesis of phosphoramidites of isoGNA, an isomer of glycerol nucleic acid

Abstract

SummaryIsoGNA, an isomer of glycerol nucleic acid GNA, is a flexible (acyclic) nucleic acid with bases directly attached to its linear backbone. IsoGNA exhibits (limited) base-pairing properties which are unique compared to other known flexible nucleic acids. Herein, we report on the details of the preparation of isoGNA phosphoramidites and an alternative route for the synthesis of the adenine derivative. The synthetic improvements described here enable an easy access to isoGNA and allows for the further exploration of this structural unit in oligonucleotide chemistry thereby spurring investigations of its usefulness and applicability.

The Role of Glycerol and Its Derivatives in the Biochemistry of Living Organisms, and Their Prebiotic Origin and Significance in the Evolution of Life

“…The prebiotic synthesis of phosphorylated derivatives of these compounds has been demonstrated [151][152][153][154][155][156][157][158][159][160][161][162][163][164], and these compounds serve as "feedstock" molecules to more complex sugars and macromolecules. Glycerol has also been demonstrated to serve as a backbone in synthetic nucleic acids as iso-GNAs [169][170][171][172][173]. These roles highlight a potential for a more independent, self-replicating system relevant to the origin of information transfer and early life ( Figure 15), with glycerol playing a central role, and less contingent on a comparatively difficult to synthesize ribose backbone.…”

“…This raises a question: were 'traditional' RNA and DNA the only plausible genetic systems in early developing life? The recent development of alternative nucleic acid systems, including that of glycerol in iso-GNA phosphoramidites, has applications in medical sciences and DNA technology, far beyond the realm of prebiotic chemistry [173]. precursors.…”

“…This is also supported by the fact that a large number of organic molecules that are used in modern biochemistry are found in the interstellar medium, comets, asteroids, meteorites, and interplanetary dust particles. It is plausible that large quantities of extraterrestrial organic compounds were delivered to the early Earth via meteorites to plausibly initiate the process of prebiotic syntheses [172][173][174][175][176][177][178][179][180][181].…”

Nucleobase coupling by Mitsunobu reaction towards nucleoside analogs

“…The versatility of 2-amino-6-chloropurine was also shown by Weising et al, 67 67 An alternative to chlorinated guanine precursors is a nucleobase embodying a diphenylcarbamate at position 6 with its 2-amino group protected with the 2-methylethylcarbonyl group. This guanine precursor was coupled to the diprotected glycerol 52 by Krishnamurthy et al 68 via MR in yields ranging from 47% to 58% (Scheme 15). This acyclic nucleoside, derived from glycerol, was prepared for its further exploration in oligonucleotide chemistry aiming to discover new nucleic acid mimetics with base-pairing properties.…”

“…Scheme 15. Synthesis of the acyclic sugar nucleoside analog 53 derived from 1,3-diprotected glycerol 52 via MR. 68 Hollenstein & Leumann 69 succeeded to couple the same nucleobase to the acyclic diol 54 through a highly regioselective MR, affording the acyclic nucleoside analog 55 in 59% yield (Scheme 16). This structure served as a precursor to access new DNA mimetics with potential binding affinity to complementary oligonucleotides.…”