Journal of the American Chemical Society We then examined the multicomponent reaction of thiazole 7, 4-amino-imidazole 5-carboxamide 16,17 and a series of aldehydes. Initially model aliphatic aldehydes were investigated to avoid issues of annulation control. Equimolar quantities of thiazole 7 and aliphatic aldehydes (including formaldehyde, acetaldehyde, propionaldehyde, and cyclobutaldehyde) with excess amino-imidazole 16 (1.2−3 equiv) furnished high yields (75−90%) of thiazolines 17, 18, 19, and 20, respectively, at pH 5. The multicomponent reactions were found to be robust at multi-gram scale and comparable diastereoselectivity was observed in the reaction of aliphatic aldehydes with oxazole 1 or thiazole 7 and amino-imidazole 16 (via imine 21 R = alkyl; d.r.= 2.5:1−4:1 threo/erythro).3 Compounds 17, threo-18 and erythro-18, and the major isomers of 19 and 20 were isolated by fractional crystallization, and the crystal structures are shown in Scheme 4.19 Scheme 4. Three-Component Reaction of 2-Aminothiazole 7, 5-Amino-imidazole-4-carboxamide 16, and Various Aliphatic Aldehydes To continue our investigation into the potential of multicomponent assembly of nucleotides we studied the participation of thiazole 7 in carbon−carbon bond-forming reaction with α-hydroxyaldehydes and imines derived from α- hydroxyaldehydes in water.20 Incubation of equimolar aldehyde 3, 2-aminothiazole 7, and amino-imidazole 16 for 5 d in water at pH 4−6 at 20 °C gave a high yield of C4-thiazoline 23 (80% isolated yield) as 1.2:1 erythro/threo mixture of diastereomeric products. Surprisingly, this signiﬁed that the facial selectivity of thiazole 7 is signiﬁcantly relaxed with respect to oxazole 1 and imine 21 (R = CH2OH). However, both erythro-23 and threo- 23 were formed with complete annulation control (>99%, see 1H NMR spectrum shown in Supporting Information Figure S28; single crystal X-ray structures of erythro-23 and threo-23 are shown in Scheme 5).22 Upon investigation of the parallel MCR with the C3-synthon glyceraldehyde 22, comparable eﬃciency in the synthesis of C5- thiazoline 24 (70% isolated yield) was observed. Again, exclusive 6-exo-trig annulation is observed; however, in this case, 24 is furnished with signiﬁcant diastereoselectivity (d.r.= 9:5:1.1:1, see Scheme 5 and Supporting Information Figure Article Scheme 5. Three-Component Reaction of 2-Aminothiazole 7, 4-Aminoimidazole-5-carboxamide 16, and Glyceraldehyde 22 S35). Isolation of the two major isomers, crystallization, and X- ray diﬀraction proved their xylo- and lyxo-conﬁguration.22 The diastereoselectivity obtained, upon carbon−carbon bond formation is proposed to result from intramolecular hydro- gen-bonding and concomitant steric impedance of thiazole addition to the Si-face of imine 21 (see Supporting Information Scheme S1).3,23 Although the facial selectivity of the nucleophile 7 has been relaxed with respect to the comparable reaction of 1, the facial selectivity of the glyceraldehyde-imine 21 (R = CH2OH) is retained.3 This is important with respect to purine nucleotide synthesis by 3′-purine tethering, which necessarily requires N3′-displacement and C3′-inversion. Furthermore, as well as regiospeciﬁc tethering of 16 and consequent delivery of N1 to the anomeric carbon atom, reaction of thiazole 7 with imine 21 regiospeciﬁcally delivers sulfur to C2′, which is of signiﬁcant interest with regards to the potential synthesis of 2′-deoxynucleotides by C2′-desulfuriza- tion. The multicomponent tricyclic thiazoline products 17−24 were uncontaminated with homoaldolization and homo- Mannich byproducts. Additionally, oxazole 1 is known to react eﬃciently with α-hydroxyaldehydes in a pH-dependent bimolecular domino-reaction.3 In striking contrast, no signiﬁ- cant carbon−carbon bond formation was observed by 1H NMR analysis upon incubation of thiazole 7 with either glycolalde- hyde 3 or rac-glyceraldehdye 22 in D2O (pD 3−9, 4−100 °C). Instead, over a period of 4 days at pD 7, crystal formation was observed from an aqueous solution containing 3 (100 mM) and thiazole 7 (100 mM) at 20 °C.24 Single crystal X-ray diﬀraction of a crystal isolated directly from the reaction supernatant proved that the structure was aminal 25 (Scheme 6).25 Though NMR studies conﬁrmed that rac-22 formed hemiaminal 26 and aminal 27 with thiazole 7 in D2O, no aminal crystallization was observed in solutions of rac-22 and 7, even at signiﬁcantly elevated concentrations (500 mM to 2M) or with substoichiometric quantities of rac-22. To test whether 13891 dx.doi.org/10.1021/ja306176n | J. Am. Chem. Soc. 2012, 134, 13889−13895