The Formose Reaction

The formose reaction is principally an aldol reaction (anionic mechanism) of formaldehyde in an aqueous solution. By a complex repetition of the reaction, the carbon chain grows, to yield a variety of monosaccharides from C2 to Cs. 

The formose reaction in detail, however, consists of a series of reactions primary self-addition of formaldehyde followed by aldol reaction of products with each odier and with formaldehyde. Cannizzaro and cross-Cannizzaro reactions occur, as well as Lobry de Bruyn-Alberda van Ekenstein rearrangements. Product decomposition (for example, to chromophores) occurs if the reaction conditions are unduly severe. The monosaccharides formed are all dl (racemic), with no optical rotatory 

A number of catalysts for the formose reaction are known (see Table I). They are mostly inorganic and organic bases. In particular, the hydroxides of alkaline-earth metals (for example, calcium hydroxide) are most effective, because of their particular ability to form stable complexes with enediol compounds (see formula 1). The reaction occurs not only in aqueous solution but also in anhydrous ethyl alcohol, glycerol, and glycol, or in solutions of organic acids, although less actively. 

Ca(OH)2 (30 g), stirring for 20 min (yellowing point) treat with 20% HjSO4(160 ml) to slight acidity 

MgSOa tetraethylammonium hydroxide 

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The formation of sugars from the reaction of formaldehyde under alkaline conditions was discovered in 1861 and is known as the formose reaction , although it is not understood fully (Figure 8.7). It requires the presence of suitable inorganic catalysts such as Ca(OH)2 or CaCOr, either of which may be found on a prebiotic Earth. The reaction is autocatalytic and produces over 40 different types of sugars, some rings, some long chains. 

The formose reaction leads to the production of many sugars with the exception of ribose, which occurs in very low concentrations and it is hard to see how this could be increased. A variation on the formose reaction starting at the phospho-rylated glycoaldehyde intermediate, with the addition of base or in the presence of mineral substrate, produced a surprisingly large amount of ribose but this still... 

Endogenous organic synthesis Urey-Miller experiments as a source of prebiotic molecules via the Strecker synthesis for amino acids, HCN polymerisation for purines and pyrimidines and the formose reaction for sugars... 

Ribose The sugar that attaches to the DNA bases to form part of the DNA backbone helical structure. The sugar is not made in the formose reaction process. 

Figure 3.6 The formose reaction. (Adapted from Miller, 1998.)...

Are there other types of self-replication in nature, possibly based on a quite different mechanism There are not many, but there is a famous case the formose reaction, described in 1861, and based on a reaction cycle of formaldehyde. This reaction has already been mentioned in Chapter 3, on the subject of prebiotic... 

Figure 7.4 Schemae of the formose reaction (a) spontaneous, slow formation of glycolaldehyde from formaldehyde (b) after one cycle, one new molecule of glycolaldehyde is produced. The structural isomers of sugars are specified by the carbon skeleton and by the position of the carbonyl group (open circle). (Adapted, with some modifications, from Maynard Smith and SzathmSry, 1995.)...

We have also learned that self-replication is not a prerogative only of nucleic acids, but it can be shared by different kinds of chemical families see the formose reaction, the self-replicating peptides, and the self-reproducing micelles and vesicles. The list should include the cellular automata and the corresponding devices of artificial life. Self-reproduction of vesicles and liposomes is important because it represents a model for cell reproduction. 

Additional advantages of the formamide condensation protocol were observed performing the reaction in the presence of catalysts which decompose formamide to formaldehyde. Formaldeyde is the most important pre-biotic precursor of sugars through a series of enolization and aldol-like condensation processes catalyzed under acidic or basic conditions, known as the formose reaction [100]. When formamide was heated at 160 °C in the presence of titanium dioxide (a catalyst able to degrade amides to aldehydes) [101] a complex mixture of nucleobase derivatives was obtained including adenine 1, purine 12, cytosine 17, N9-formylpurine 28, N9, N6-diformyladenine 29, 5-hydroxymethyluracil 30, thymine 31 and three novel... 

Intermediates of the formose reaction can yield amino acids in the presence of ammonia and thiols [61,62] through a process that will be examined in more details in subsequent sections (see Sect. 3.4.2) since amino-thioesters are activated peptide precursors. 

Weber [61,62] has developed in the context of prebiotic chemistry an original pathway for a-aminothioester synthesis [180], which can start from hydroxyaldehydes 30 intermediates in the formose reaction (a likely prebiotic pathway to carbohydrates). Obviously, thioesters themselves are not observed as products because of their fast hydrolysis in the medium, but they could be converted into peptide bonds in the presence of amino acids or peptide free amino groups, and into mixed anhydride with phosphoric acid in the presence of inorganic phosphate. The reaction involves two key-steps the condensation of ammonia and of the mercaptan on a-keto aldehyde 31... 

One experimental approach would be to generate heterogeneous vesicles in broths containing the constituents of the formose reaction, initially limiting the concentration of formaldehyde. After leaving the system for a while, formaldehyde would be added to the solution. Those vesicles that grew and divided fastest would be selected for. There may be rare conditions under which the constituents of the formose reaction are permeable to the membrane. They enter the vesicle and become trapped as soon as those conditions change. Formaldehyde could then enter the vesicles and allow the autocatalytic cycle to run. 

See, for example, Breslow R., 1959, On the mechanism of the formose reaction, Tetrahedron Lett. 21 22-26 Butlerow, A., 1861, Bildung einer zuckerartigen Substanz durch Synthese. Annalen 120 295-298 and Ricardo, A., Carrigan, M.A., Olcott, A.N., and Benner, S.A., 2004, Borate minerals stabilize ribose, Science 303 196. 

Solutions of that type are improbable. In exchange for a simplification mixture of the formose reaction, we must specify the presence of glycolaldehyde, glyceraldehyde, and borate minerals (and the absence of many potentially interfering substances, such as cyanide) and a route by which the protective borate will be removed so that the route to oligonucleotide formation remains open. Ribose is only one of the six components present in RNA. An extended number of steps involving the synthesis, purification, transportation, and highly specific... 

Although there are a number of inefficient steps in most proposed prebiotic syntheses of ribotides, the major objection to RNA as the primogenitor of life has been the relatively small yield of ribose in the formose reaction, a simple condensation of glycoaldehyde. Muller et a/.,18 however, have discovered a variation of the formose reaction that produces a limited mix of pentose diphosphates in which the ribose forms predominate (52 14 23 11, ribose arabinose lyxose xylose). Although many critical chemical roadblocks remain (such as the extremely low yield of pyrimidine nucleosides following the condensation of ribose and free bases), this advance belies the previously held view that products of the formose reaction are necessarily so chemically diverse that they are the carbohydrate analog of petroleum. 19... 

First, the question of where nucleotide monomers may have come from is critical. Given that the formose reaction is the most likely candidate for the synthesis of prebiotic ribose, but yields very little pure material, the role of stereoselective catalysts (clays, amino acids, or lipid aggregates) in directing the reaction should be fully explored. In this respect, Wachters-hauser16 has advanced a scheme for nucleotide synthesis based on pyrite catalysis than can be readily tested. 

In the presence of formaldehyde (0.5 mol equiv.), sugar phosphates were formed in up to 45% yield, with pentose-2,4-diphosphates dominating over hexose triphosphates by a ratio of 3 1 (Scheme 13.2, Route B). The major component was found to be D,L-ribose-2,4-diphosphate with the ratios of ribose-, arabinose-, lyxose-, and xylose-2,4-diphosphates being 52 14 23 11, respectively. The aldomerization of 2 in the presence of H2CO is a variant of the formose reaction. It avoids the formation of complex product mixtures as a consequence of the fact that aldoses, which are phosphorylated at the C(2) position, cannot undergo aldose-ketose tautomerization. The preference for ribose-2,4-diphosphate 5 and allose-2,4,6-triphosphate formation might be relevant to a discussion of the origin of ribonucleic acids. 

Shigemasa, Y, Ueda, T, Saimoto, H, First synthesis of DL-2-C-hydroxymethyl-3-pentulose in the formose reaction, J. Carbohydr. Chem., 8, 669-673, 1989. 

The formose reaction has been investigated using immobilized thiazolium catalyst [26]. Under these conditions the main products are dihydroxyacetone (DHA), erythrulose, and 4-hydroxymethyl-2-pentulose. The relative importance of these products depends on the amount of thiazolium salts and concentration in 1,4-dioxane [27,28,29]. A possible mechanism implies the Stetter reaction [30,31,32,33,34]. 

The quest for synthetic routes to ribose continued. The reduction of the high pH in the formose reaction was made possible by adding Mg(OH)2 the aldopentoses obtained were more stable, but the reaction was slower. The search for more effective catalysts led to Pb2+ ions. The first mention of this possibility was made by Wolfgang Langenbeck (University of Halle) as early as 1954 (Langenbeck, 1954). 

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