Potentially Prebiotic Synthesis of a 3′-Amino-3′-deoxyribonucleoside

A central challenge in origins-of-life research is to elucidate how primitive genetic polymers could have replicated and propagated nonenzymatically before the advent of macromolecular catalysts. Nucleosides and nucleotides are considered to be essential for the emergence of life, rendering their prebiotically plausible synthesis of fundamental importance. Several potentially prebiotic pathways have been demonstrated for the formation of genetic polymers, such as RNA, DNA, threose nucleic acids (TNA), and arabinose nucleic acids (ANA). More recently, the prebiotic assembly of 3'-amino-TNA nucleosides has been achieved, whereas the analogous 3'-amino-RNA has remained elusive. Here, we report a potentially prebiotic route to 3'-amino-3'-deoxy-2-thiocytidine starting from simple feedstock molecules. Although the key intermediate, 3'-amino-ribose-aminooxazoline, undergoes degradation over the period of days, as previously observed, we demonstrate that cyanovinyl protection via cyanoacetylene treatment suppresses the byproduct formation and enables the successful synthesis of the 3'-amino-3'-deoxy-anhydrocytidine intermediate. We further show that the cyanovinyl protecting group is compatible with thiolysis at the 2-position and is concurrently removed during this process. Finally, photoanomerization of the α-anomer affords the desired β-3'-amino-3'-deoxy-2-thiocytidine. These findings support the hypothesis that 3'-amino-modified ribonucleotides could have existed under prebiotic conditions on early Earth.