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The Origins of Nucleotides.Pdf 1956 SYNPACTS The Origins of Nucleotides TheMatthew Origins of Nucleotides W. Powner,*a John D. Sutherland,b Jack W. Szostaka a 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, USA Fax +1(617)6433328; E-mail: [email protected] b MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK Received 18 April 2011 This paper is dedicated to the memory of Leslie Orgel, a greatly missed colleague and a true pioneer of prebiotic chemistry Abstract: The origins of life represent one of the most fundamental chemical questions being addressed by modern science. One of the longstanding mysteries of this field is what series of chemical reac- tions could lead to the molecular biologists dream; a pool of homo- chiral nucleotides? Here we summarize those results we consider to be historically important and outline our recently published re- search aimed at understanding the chemoselective origins of the canonical ribonucleotides. 1 Introduction 1.1 Nucleotides: What’s the Problem? 2 Synthesis of Activated Pyrimidines Matthew W. Powner (left) obtained his MChem in chemistry at the 2.1 Pyrimidine Elaboration by Cyanovinylation University of Manchester, and also his PhD in organic chemistry wor- 2.2 Photochemical Epimerization and Cytidine to Uridine king with Prof. John. D. Sutherland. He continued his research at Conversion Manchester as an EPSRC PhD plus fellow, before moving to the la- 2.3 Urea-Mediated Phosphoryl Transfer and Intramolecular boratory of Prof. Jack Szostak as postdoctoral fellow at Harvard Me- Rearrangement dical School and Massachusetts General Hospital. His research 2.4 Pyrimidine Photosanitization interests include the chemical origins of life, pH-controlled reactivity, 3 Chemoselective Purine Glycosylation and multicomponent reactions. John D. Sutherland (center) studied 4 Future Scope for Investigation chemistry at the University of Oxford under the tutelage of Peter 5 Conclusion Atkins and Gordon Lowe, and then spent a spell as a Kennedy Scholar Key words: nucleotides, chemoselectivity, multicomponent reac- at Harvard with Jeremy Knowles. Upon return to the UK, he carried tions, rearrangement, photochemistry out his doctoral work with Jack Baldwin at Oxford, and then stayed in Oxford first as a Junior Research Fellow and then as a University Lecturer in Organic Chemistry. In 1998 he took a chair in Biological Chemistry at Manchester, and in 2010 moved to the MRC Laboratory 1 Introduction of Molecular Biology in Cambridge as a Group Leader. He is inter- ested in chemistry associated with the origin of life, and in evolution. Jack W. Szostak (right) carried out his doctoral research on nucleic The discovery of the biochemical unity of life, which be- acids under the supervision of Prof. Ray Wu at Cornell University, lies the more obvious biological diversity, first led to the then stayed on to study yeast genetics as a postdoctoral fellow. In idea of a chemical origin of life.1 As early as 1828, Wöhler 1979 he started as an Assistant Professor of Biological Chemistry at reported the synthesis of the organic molecule urea from Harvard Medical School. He is currently an Investigator of the Downloaded by: University of Oxford. Copyrighted material. inorganic materials,2 a defining point for both synthetic Howard Hughes Medical Institute, Professor of Genetics at Harvard Medical School, and the Alex Rich Distinguished Investigator in the chemistry and the recognition of the potential of chemis- Department of Molecular Biology and the Center for Computational try to transition into biology. However, abiogenesis re- and Integrative Biology at Massachusetts General Hospital. His re- mains one of the most basic chemical problems to be search interests include the laboratory synthesis of self-replicating addressed by modern science.3 We have therefore set out systems and the origin of life. to extend our knowledge of the organic chemistry of po- tential relevance to this question. abiogenesis. The oligomerization of hydrogen cyanide was an early subject of study.5 The near-quantitative pho- The discovery of the deep-seated relationship between nu- ton-induced intramolecular rearrangement of diaminoma- cleotides and the transfer of genetic information led to the leonitrile (1), a major product of HCN oligomerization, to first suggestions, in the mid-twentieth century, that RNA 5-amino-imidazole-4-carbonitrile (2) and subsequent hy- may have played a central role in the early evolution of drolysis to 5-amino-imidazole-4-carboxamide (3) were 4 life. At that time several laboratories made significant both demonstrated (Scheme 1). However, further elabora- empirical advances towards understanding nucleotide tion of 2 or 3 to purine nucleobases and purine nucleotides were both very low yielding.6 Thus, despite recent ad- SYNLETT 2011, No. 14, pp 1956–1964 xx.xx.2011 vances in aqueous pentose synthesis and continued efforts 7,8 Advanced online publication: 10.08.2011 to ribosylate nucleobases, the formation of adenosine DOI: 10.1055/s-0030-1261177; Art ID: P01611ST (and inosine) is in very low yield and, more importantly, © Georg Thieme Verlag Stuttgart · New York SYNPACTS The Origins of Nucleotides 1957 occurs alongside the synthesis of a multitude of regio- and scribe substantial progress towards the chemoselective, pyranosyl isomers. Furthermore, guanine, cytosine, and prebiotically plausible synthesis of activated pyrimidine uracil do not yield any of their respective nucleosides un- nucleotides,11 and the initial results from an investigation der similar glycosylation conditions.7 Orgel et al. reported toward purine synthesis.12 Our approach has been based several highly interesting observations with regards to upon an incremental accumulation of knowledge, with our pyrimidine synthesis and these formed a significant part attention directed to the discovery of high-yielding chem- of the inspiration for our original studies.9 However, low ical transformations. Initially we focused our investiga- yields, serious chemo-, regio-, and diastereoselectivity is- tions upon isolated subsystems of chemicals – perceived sues, and no reasonable procedure for the production or to be relevant as a result of retrosynthetic analysis – with isolation of ribose – the key component of their retrosyn- a view to the ultimate realization of complete, self- thetic analysis – plagued their synthesis. This led to the controlled reaction pathways, and larger chemical sys- prevailing opinion that ‘… it is possible that some efficient tems. We avoid the temptation of attempting to analyze prebiotic synthesis of the b-ribosides, or some method of extremely complex mixtures of products from high- separating the b-ribosides from closely related isomers, energy reactions, wherein yields are incredibly low, and will be discovered, but there is no basis in organic chem- the generation of inordinate numbers and ranges of prod- istry for optimism.’10 ucts is chemically uncontrolled. O R HO R H 3 HCN NH2 HN 2 Synthesis of Activated Pyrimidines R = H, Alk N N Pur = purine The most important aspect of the pyrimidine synthesis N pathway developed in the Sutherland laboratory is that it avoids several major problems of the traditional retrosyn- RCHO – RCHO thetic analysis (sugar + nucleobase + phosphate), while al- lowing the stepwise construction of both canonical NH2 N pyrimidine ribonucleotides in five robust steps. First, the 3 HCN H2N hν N HCN HN N general acid-base catalyzed formation of 2-aminooxazole 4 NH2 ( ) is mediated at neutral pH by phosphate, which also N catalyzes the hydration of excess cyanamide to urea (an 1 2 important point vide infra).11a Phosphate is present throughout the reaction sequence since it is a necessary re- O agent for the synthesis of nucleotides. In the early steps it O Pur N O acts as catalyst or buffer, but its potential as a reagent is not expressed until later. We therefore consider it to be a HN O OH NH2 latent reagent. Carbon–carbon bond formation, upon ad- P NH2 dition of 4 to glyceraldehyde, results in construction of the O 3 O n five-carbon pentose backbone with complete furanosyl Scheme 1 Hydrogen cyanide oligomerization selectivity and regiospecific glycosylation in one step (Scheme 2).11a,13 O O N N N H Downloaded by: University of Oxford. Copyrighted material. 2 + OH H O, H NaPO NH H N NH 2 2 4 O 1.1 Nucleotides: What’s The Problem? 2 2 2 pH 7, >90% The problem of abiotic synthesis, with respect to each of 4 OH the four canonical ribonucleotides, is the sum of nine re- O H O, H NaPO 2 4 quired chemoselectivities. The canonical nucleotides 2 must be: 1. aldose not ketose; 2. pentose not tetrose, hex- pH 7, >95% ose, etc; 3. ribo, not arabino, lyxo, or xylo; 4. furanosyl not OH HO pyranosyl; 5. b not a; 6. D not L; 7. regiospecifically gly- HO O O cosylated; 8. regiospecifically phosphorylated; 9. activat- spontaneous N N ed (or activatable) toward regiospecific oligomerization. crystallization NH NH 2 2 O O HO Each of these requirements must ultimately be satisfied by HO the inherent chemoselectvity and predisposed reactivity 5 of abiotic chemical space, without requiring enzymatic control, chiral pool reagents, chromatography, or an ex- Scheme 2 General acid-base catalyzed aqueous synthesis of 2-ami- nooxazole (4) and in situ formation and crystallization of ribose ami- perimenter. Ideally, a divergent synthesis in the absence nooxazoline (5) of other molecules capable of both polymerization and Watson–Crick base pairing is required. Towards this end, Additionally, although several pentose syntheses have our laboratories have published a series of papers that de- been reported, our observed diastereoselectivity is the Synlett 2011, No. 14, 1956–1964 © Thieme Stuttgart · New York 1958 M. W. Powner et al. SYNPACTS highest ribo/arabino selectivity (44:30, >95% yield) re- HO ported in the literature. For example, Kofoed et al. report HO O O N a lyxo-selective Zn(Pro)2-catalyzed pentose synthesis N 8i NH from glycolaldehyde and glyceraldehyde.
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