Here is a puzzle: in what area of organic synthesis research are synthetic organic chemists a minority? According to Albert Eschenmoser,(1) it is in the field of prebiotic chemistry: the study of the reactions and molecules that led to the emergence of life on earth. Biologists, mathematicians, and astronomers have traditionally weighed in on this problem proportionally more than organic chemists. When chemists do play in this field, they are venerable—Albert Eschenmoser, Leslie Orgel, Jack Szostak, and Ronald Breslow, to name a few—but only rarely has the field been the province of early career organic chemists. It may be that the challenge of finding funding for such an esoteric problem comes easier to established scientists in a world increasingly focused on practical applications. But a desire to explore this field also speaks to the uniquely reflective mindset required to contemplate the greatest retrosynthetic analysis of all, leading us from modern enzymes and genetic polymers back to the etiology of biomolecules. A glimpse into this kind of thinking is provided in a recent Nature Chemistry paper(2) by Adam J. Coggins and Matthew W. Powner, along with a 2015 Nature Chemistry paper(3) by John D. Sutherland and co-workers.

A uniquely reflective mindset is required to contemplate the greatest retrosynthetic analysis of all, leading us from modern enzymes and genetic polymers back to the etiology of biomolecules.

Probing plausible prebiotic chemistry requires an extraordinary combination of outlook and expertise that differs subtly from that employed in other areas of organic synthesis. For example, rather than seeking to develop novel synthetic methodologies and complex molecular architectures, origin-of-life researchers must look to unlock the secrets of ancient and simple processes that might have been available to construct the building blocks of life in a primordial world. The principal authors of these two Nature Chemistry papers, Powner and Sutherland, also authored (along with Beatrice Gerland) the breakthrough 2009 Nature paper(4) demonstrating a prebiotically plausible route to activated pyrimidine ribonucleotides, thus solving a long-standing conundrum of the “RNA World” hypothesis.(5) That work comprised Powner’s PhD studies with Sutherland, who, largely inspired by Eschenmoser and unusually for this field, has from the start dedicated his career to synthetic prebiotic chemistry. Powner seems set to do the same.

The “vestiges of an earlier reactivity” point to α-phosphorylation instead of terminal phosphorylation in the glycolytic and other protometabolic pathways.

The 2016 Powner work tackles the problem of how metabolism could have evolved from reactions of simple organic molecules prior to the emergence of complex enzymatic processes. The focus is on glycolysis with an emphasis directed toward the synthesis of phosphoenol pyruvate (1): a high-energy, versatile, and ubiquitous molecule in modern metabolism (1 in Scheme 1). Nailing down a plausible nonenzymatic synthetic route to this key intermediate would be an important step in unwinding protometabolic pathways.

Scheme 1 Scheme 1. Enzymatic and Protometabolic Approaches to Glycolysis (2)

Starting with glyceraldehyde 3, Powner builds on Krishnamurthy et al.’s report(6) of regioselective phosphorylation with amidotriphosphate using magnesium by showing that the same outcome can be achieved with phosphate buffer at neutral pH to produce glyceraldehyde-2-phosphate (3-2P). The authors then show that a variety of prebiotically relevant oxidation systems can produce the desired compound 1 as well as 2-phosphoglyceric acid (4-2P).

Powner’s thinking works its way backward from enzymes such as the highly evolved TIM (triose phosphate isomerase), known from Jeremy Knowles’s elegant work as a nearly “perfect” catalyst,(7) to what Powner calls the “vestiges of an earlier reactivity” based on α-phosphorylation instead of terminal phosphorylation. At first glance, access to the downstream intermediates in the glycolysis pathway is problematic in nonenzymatic metabolism. The first intermediate after C 6 metabolites is glyceraldehyde-3-phosphate (3-3P), which isomerizes to the more thermodynamically stable dihydroxyacetone phosphate (21-P) with an equilibrium ratio of 20:1. In a prebiotic world where TIM does not exist to accelerate rates to the point of diffusion control, a buildup of 21-P would lead to deleterious pathways. Lacking exquisite enzymatic control, the prebiotic world may have chosen the detour via the 2-phosphate to phosphoenol pyruvate in coordinating the first steps toward the biosynthesis of amino acids, sugars, nucleic acids, and lipids.

One of the great mysteries of prebiotic chemistry is picturing how disparate chemical systems that each may explain one small part of the complexities that lead to life could possibly fit in with the rest. For this reason it is valuable to consider this work through the lens of other feats in prebiotic synthesis. Specifically, the 2015 Sutherland work(3) develops a geochemical scenario based on what he calls a “cyanosulfidic” chemical homologation theme that can provide the building blocks for the three key subsystems of informational, compartment-forming, and metabolic molecules. Scheme 2 summarizes his grand symphony in four movements(8) that leads with startling efficiency to the building blocks of RNA, proteins, and lipids, relying on hydrogen cyanide as the sole carbon and nitrogen source, hydrogen sulfide as a reductant, and ultraviolet light and Cu(I)/Cu(II) catalysis of photoredox cycling.

Scheme 2 Scheme 2. “Big Picture” of the Interconnections between Prebiotic Syntheses of Ribonucelotide, Amino Acid, and Lipid Precursors (see Ref 3

This grand symphony in four movements (summarized in Scheme 2) leads with startling efficiency to the building blocks of RNA, proteins, and lipids, relying on hydrogen cyanide as the sole carbon and nitrogen source.

Reductive homologation of HCN (movement a) provides the C2 and C3 sugars needed for subsequent ribonucleotide assembly as well as precursors to amino aicds Gly, Ala, Ser, and Thr. Reductive homologation of the products of glyceraldehyde isomerization and reduction leads to lipid precursors as well as amino acids Val and Leu (movement b). Cu(I) catalyzed cross-coupling followed by reductive homologation gives precursors of Pro and Arg (movement c), while Cu(II) driven oxidative cross-coupling leads to precursors of Gln, Glu, Asn, and Asp (movement d).

This simple scenario culminates inexorably in the very set of molecules used by modern biology. Sutherland counters potential criticism of the lack of feasibility of a simultaneous “one-pot” system by describing, convincingly, how different components may be delivered at different times and places via pools and streams, rainfall, and evaporite basins.(9) Not only does this description implicate our set of proteinogenic amino acids as preordained for life, it also overcomes perceived incompatibilities between the key subsystems and suggests that they could have developed together rather than sequentially.

Both Powner and Sutherland are quick to concede that the picture emerging from these studies must still be painted with “broad brushstrokes”,(3) but the recent advances that have been made in our understanding of how the prebiotic world may have facilitated the origin of life are compelling. Parallel efforts focused more narrowly on stereochemical considerations of biomolecules have also advanced significantly,(10) prompting a Chemistry World quote that we may now be “spoilt for choice”(11) in models of how biological homochirality evolved. Perhaps the inevitability of the emergence of life from a protometabolism as described in the ongoing work of organic chemists like Powner and Sutherland will become apparent soon enough.

Funding Information Funding from the Simons Foundation Collaboration on the Origins of Life (SCOL 287625) is acknowledged. References ARTICLE SECTIONS Jump To This article references 11 other publications. 1 Eschenmoser, A. The search for the chemistry of life’s origins Tetrahedron 2007 , 63 , 12821 – 12844 DOI: 10.1016/j.tet.2007.10.012 2 Coggins, A. J. ; Powner, M. W. Prebiotic synthesis of phosphoenol pyruvate by a-phosphorylation-controlled triose glycolysis Nat. Chem. 2016 , DOI: 10.1038/nchem.2624 3 Patel, B. H. ; Percivalle, C. ; Ritson, D. J. ; Duffy, C. D. ; Sutherland, J. D. Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism Nat. Chem. 2015 , 7 , 301 – 307 DOI: 10.1038/nchem.2202 4 Powner, M. W. ; Gerland, B. ; Sutherland, J. D. Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions Nature 2009 , 459 , 239 – 242 DOI: 10.1038/nature08013 5 While ribose and nucleotides have been separately synthesized, no prebiotically plausible means of constructing ribonucleotides by coupling the two had been demonstrated. The work in ref 4 circumvented this problem by reacting 2-aminooxazole with glyceraldehyde to produce riboaminooxazoline, which was converted in a further step to the activated ribonucleotide. 6 Krishnamurthy, R. ; Guntha, S. ; Eschenmoser, A. Regioselective a-phosphorylation of aldoses in aqueous solution Angew. Chem., Int. Ed. 2000 , 39 , 2281 – 2285 DOI: 10.1002/1521-3773(20000703)39:13<2281::AID-ANIE2281>3.3.CO;2-U 7 Albery, W. J. ; Knowles, J. R. Efficiency and evolution of enzyme catalysis Angew. Chem., Int. Ed. Engl. 1977 , 16 , 285 – 293 DOI: 10.1002/anie.197702851 8 The physicists and astronomers participating in the Simons Foundation sponsored Simons Collaboration on the Origins of Life (SCOL) refer to the full version of Scheme 2 presented in ref 3 as “the revenge of the chemists” figure. 9 Although Sutherland calls this a “flow chemistry” scenario, I believe a phrase such as “sequential connected compartmentalization” is more apt, in order to avoid a potentially misleading analogy to modern pharmaceutical flow processes. Indeed, if modern process terms are to be invoked, this scenario is closer to “semi-batch” operation than to typical flow systems. 10 (a) Blackmond, D. G. The Origin of Biological Homochirality Cold Spring Harbor Perspect. Biol. 2010 , 2 , a002147 DOI: 10.1101/cshperspect.a002147 (b) Hein, J. E. ; Blackmond, D. G. On the Origin of Single Chirality of Amino Acids and Sugars in Biogenesis Acc. Chem. Res. 2012 , 45 , 2045 – 2054 DOI: 10.1021/ar200316n 11 Ball, P. Giving Life a Hand . Chem. World 2007 , March 20 .

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