Article pubs.acs.org/JACS Multicomponent Assembly of Proposed DNA Precursors in Water Matthew W. Powner,*,†,§ Shao-Liang Zheng,‡ and Jack W. Szostak § †Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London, WC1H 0AJ, U.K. ‡Harvard X-ray Crystallography Centre, 12 Oxford Street, Cambridge, Massachusetts 02138, United States §Howard Hughes Medical Institute and Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States *S Supporting Information ABSTRACT: We propose a novel pathway for the prebiotic synthesis of 2′-deoxynucleotides. Consideration of the constitutional chemical relationships between glycolaldehyde and β-mercapto-acetaldehyde, and the corresponding protei- nogenic amino acids, serine and cysteine, led us to explore the consequences of the corresponding sulfur substitution for our previously proposed pathways leading to the canonical ribonucleotides. We demonstrate that just as 2-aminooxazole−an important prebiotic ribonucleotide precursor−is readily formed from glycolaldehyde and cyanamide, so is 2-aminothiazole formed from β-mercapto-acetaldehyde and cyanamide in water at neutral pH. Indeed, both the oxazole and the thiazole can be formed together in a one-pot reaction, and can be co- puriﬁed by crystallization or sublimation. We then show that 2-aminothiazole can take part in a 3-component carbon−carbon bond-forming reaction in water that leads to the diastereoselective synthesis of masked 2′-thiosugars regiospeciﬁcally tethered to purine precursors, which would lead to 2′-deoxynucleotides upon desulfurization. The possibility of an abiotic route to the 2′- deoxynucleotides provides a new perspective on the evolutionary origins of DNA. We also show that 2-aminothiazole is able to sequester, through reversible aminal formation, the important nucleotide precursors glycolaldehyde and glyceraldehyde in a stable, crystalline form. ■ INTRODUCTION A plausible abiotic chemical route to the canonical nucleotides is a major goal in origins of life research.1−3 Recently, we demonstrated the ﬁrst chemical steps toward a divergent pyrimidine and purine ribonucleotide synthesis.3 A one-pot multicomponent reaction was demonstrated to stereoselectively tether and consequently regiospeciﬁcally glycosylate purine precursors and masked pentose sugars, while concurrently furnishing known pyrimidine precursors (Scheme 1). Scheme 1. Proposed Multicomponent Ribonucleotide Syntheses Although RNA has often been considered as a candidate for the ﬁrst biopolymer of life,1,2 extant biology utilizes two chemically distinct, but related, nucleotide polymers, RNA and DNA. DNA is usually viewed as a late evolutionary adaptation of earlier RNA-based life.4 However, it would not be possible to make DNA without deoxyribonucleotides, and yet in the absence of DNA there is no obvious reason for the evolution of the biochemical pathways for the synthesis of deoxyribonucleo- tides. Only after the emergence of DNA as an important cellular component would there have been a strong selective pressure favoring the emergence of biochemical pathways for the synthesis of deoxyribonucleotides from ribonucleotides. Although the advantages of DNA as a medium for information storage are clear, there has not until now been any reasonable hypothesis for how DNA could be ‘invented’ by primitive cells in the absence of pre-existing deoxyribonucleotides. In this paper, we propose a hypothesis for the prebiotic synthesis of 2′- deoxyribonucleotides. Biochemically, 2′-deoxyribonucleotides are synthesized by chemo- and regio-speciﬁc reduction of ribonucleotides.5 In the absence of the complex and energetically costly enzymatic resources required to regiospeciﬁcally deoxygenate ribonucleo- tides, abiological 2′-deoxygenation of nucleotides requires site- Received: June 28, 2012 Published: July 27, 2012 © 2012 American Chemical Society 13889 dx.doi.org/10.1021/ja306176n | J. Am. Chem. Soc. 2012, 134, 13889−13895