Journal of the American Chemical Society speciﬁc ribo- or arabino-nucleoside deoxygenation. In light of the diﬃculty of regioselective nucleotide deoxygenation in the absence of sophisticated enzymatic control, it would seem that regiospeciﬁc positioning of a group/atom with the appropriate latent potential reactivity could form the basis of an alternative pathway to the 2′-deoxyribonucleotides. In principle, a suﬃciently chemoselective reactivity diﬀerence could be exploited to generate both ribonucleotides and 2′-deoxyribo- nucleotides, simultaneously. ■ RESULTS AND DISCUSSION Constitutional analysis of DNA, with respect to RNA, in light of the low dissociation energy of C−S bonds,6 suggests that regiospeciﬁc positioning of sulfur at C2′ could result in the chemical diﬀerentiation required for the divergent synthesis of DNA and RNA monomers from common precursors (Scheme 2). Scheme 2. Proposed Multicomponent Deoxyribonucleotide Syntheses Oxazole 1−a key ribonucleotide precursor−is derived from cyanamide 2 and glycolaldehyde 3.1,3,7 The C2-carbon atom of aldehyde 3 is formally delivered to a ribonucleotide as the C2′ sugar carbon. It is of note that aldehyde 3 is also the aldehyde precursor of serine 4, a proteinogenic amino acid, via Strecker synthesis with ammonium cyanide (Scheme 3).8 The constitu- tional similarity of serine 4 and cysteine 5, and their aldehyde precursors 3 and β-mercapto-acetaldehyde 6, suggests that both 3 and 6 must be considered within our exploration of prebiotic azole synthesis.9 Speciﬁcally, we propose that the divergent Scheme 3. Constitutional Analysis: Strecker-Type Synthesis of Amino Acids (Red Box) and Azole Synthesis in Water (Blue Box) Article reactivity of glycolaldehyde 3 and β-mercapto-acetaldehyde 6 with cyanamide 2 could lead, via 2-aminooxazole 1 and 2- aminothiazole 7, to ribonucleotides1,3 and 2′-deoxyribonucleo- tides, by desulfurization of C2′ (Scheme 2).10,11 The importance of 2-aminothiazole 7, and its derivatives, has been recognized in medicinal chemistry,12 but though the synthesis of thiazole 7 in water has been reported,13 the potential relevance of thiazole 7 to the origins of life remains unexplored. The formation of oxazole 1 from cyanamide 2 and glycolaldehyde 3 at neutral pH requires stoichiometric (or excess) cyanamide 2 and general acid−base catalysis.1 Aldehyde 6, upon imine formation with cyanamide 2, has, like 3, the potential to undergo 5-exo-dig cyclization to furnish imine 14 (or hemiaminal 15) as shown in Scheme 3. Furthermore, we expected the reaction to proceed more rapidly at neutral pH and be less prone to stall at intermediates en route to thiazole 7 due to the increased nucleophilicity of sulfur and greater aromaticity of thiazoles with respect to oxazoles. To test this supposition, β-mercapto-acetaldehyde 6 (8.5 mM) and 2 (15, 26, or 50 mM) were incubated in D2O at pD 7 and 20 °C and a rapid (ca. 10 min) quantitative conversion of aldehyde 6 to hemiaminal 15 was observed (see the Supporting Information Figure S1). Over the course of several hours, 15 dehydrated to furnish thiazole 7 (see Supporting Information Figures S2 and S3).14 It is of note that excess aldehyde 6 did not lead to further reaction of thiazole 7. Moreover, at elevated concentration (>150 mM) 2-aminothiazole 7 was observed to directly crystallize from water, and a crystal structure of thiazole 7 is shown in Scheme 3.15,16 Next we investigated the concomitant synthesis of oxazole 1 and thiazole 7. In the presence of excess cyanamide 2 (2.2−5 equiv), rapid and stoichiometric conversion of glycolaldehyde 3 (1 equiv) and β- mercapto-acetaldehyde 6 (1 equiv) to hemiaminals 11 and 15, respectively, was observed in water. At high pH/pD (pH/pD > 9) speciﬁc base catalysis or in 1 M phosphate solution (pH/pD 6.5−7.5) general acid−base catalysis furnish oxazole 1 and thiazole 7 over the course of 24−36 h at ambient temperature (Scheme 3; see Supporting Information Figure S8−S10).13 At neutral pD, selective dehydration of 15 to liberate thiazole 7 was observed. Limiting cyanamide 2 (2/3/6 ∼ 0.8:1:1) also resulted in the speciﬁc generation of thiazole 7, even in 1 M phosphate solution (pH 7; See Supporting Information Figure S9). It is likely that the rapid 5-exo-dig cyclization of imine 12/ hemiaminal 13 leads to the selective sequestration of cyanamide 2 in thiazole 7. We did not observe signiﬁcant homo- and hetero-aldol reaction during the reaction of glycolaldehyde 3 and mercaptoacetaldehyde 6 with either excess or limiting cyanamide 2 between ambient temperature and 60 °C in 1 M phosphate solution at pH 7. Interestingly, we also found that, like oxazole 1, thiazole 7 is easily sublimed (see Supporting Information Figure S4), suggesting possible geo- chemical routes to the distribution, separation, and puriﬁcation of thiazole 7 under abiotically plausible conditions. Sublimation from a mixture of oxazole 1 and thiazole 7 resulted in the isolation of both azoles as colorless crystalline solids. Partial sublimation of a mixture of oxazole 1 and thiazole 7 (1:1) resulted in the isolation 4:1−2:1 oxazole 1/thiazole 7, at 50 °C between 1 and 24 h at ambient pressure, indicating the more rapid but comparable sublimation rate of oxazole 1 relative to thiazole 7. Complete sublimation was observed after 2 d at 60 °C to aﬀord ∼1:1 mixture of crystalline azoles at ambient pressure. 13890 dx.doi.org/10.1021/ja306176n | J. Am. Chem. Soc. 2012, 134, 13889−13895