Three-Carbon Fragments

The cyclization of 6-aminouracils with three-carbon fragments such as a,B- unsaturated carbonyl compounds, /3-dicarbonyl compounds, acetylenic esters, etc., is dealt with as a [3+3] reaction (see Section 2.15.5.7.2). Reactions with alkoxymethylenemalonates and related compounds are regarded as proceeding through [6 + 0 (y)] cyclizations (see Section 2.15.5.4.2). 

The concentration of ozone taken up by the media containing linolenic acid is plotted against time after addition in Figure 8. The rate of ozone breakdown is constant (ozone uptake linear with time) for the first two min until about 0.12 ml ozone are absorbed and then the rate decreases sharply, reaching a steady-state rate of ozone uptake between 10-12 min. This first break in the curve corresponds to an ozone uptake of 0.12 ml + (24 moles/liter) = 0.005 millimoles (or 10 M). This is equivalent to 1 mole of linolenic acid added per mole ozone absorbed. Thiobarbituric acid reactant production is also plotted on the same axis. This compound (TBA reactant) probably arises by formation of a three-carbon fragment (malondialdehyde) from the ozone-induced oxidation of linolenic acid (23). The rate of TBA reactant formation is also linear for the first 2 min at which point the curve undergoes a less pronounced break. Malondialdehyde formation ceases immediately when the ozone is shut off (Scrub 1 on). An oxygen control sample produced no malondialdehyde. 

The carbanion of the remaining three-carbon fragment is proto-nated by the nearby side chain of Lys175, generating a second molecule of 3-phosphoglycerate. The overall reaction therefore accomplishes the combination of one C02 and one ribulose 1,5-bisphosphate to form two molecules of 3-phosphoglycerate, one of which contains the carbon atom from C02 (red). 0 Rubisco Mechanism Rubisco Tutorial... 

The electrophilic sites in 3-nitrochromone (82) provide a three-carbon fragment for cyclization of 5-aminopyrazoles. A mechanism has been suggested (Scheme l).96... 

Six-membered rings are formed by reaction of a three-carbon fragment with an aza heterocycle containing any of (i) an a-methyl, (ii) an a-amino or (iii) a potential a-mercapto group. Examples of... 

This annulation has invariably been made by reaction of 3-amino-1,2,4-triazole derivatives with three-carbon cyclizing fragments. The three-carbon fragments may be incorporated in one step or in two consecutive steps as schematically represented in Schemes 26 and 27, respectively. 

Cyclization of 3-Amino-l,2,4-triazoles by Reaction with Appropriately Functionalized Three-Carbon Fragments... 

Reaction 2 of Fig. 17-7 is a simple isomerization that moves the carbonyl group to C-2 so that (1 cleavage to two three-carbon fragments can occur. Before cleavage a second phosphorylation (reaction 3) takes place to form fructose 1,6-bisphosphate. This ensures that when fructose bisphosphate is cleaved by aldolase each of the two halves will have a phosphate handle. This second priming reaction (reaction 3) is the first step in the series that is unique to glycolysis. The catalyst for the reaction, phosphofructokinase, is carefully controlled, as discussed in Chapter 11 (see Fig. 11-2). 

Figure 17-8 The pentose phosphate pathways. (A) Oxidation of a hexose (C6) to three molecules of C02 and a three-carbon fragment with the option of removing C3, C4, C5, and C7 units for biosynthesis (dashed arrows). (B) Non-oxidative pentose pathways 2 1/2 C6 —> 3 C5 or 2 C6 —> 3 C4 or 3 V2C6 —> 3 C7.

As was pointed out in Chapter 10, routes of biosynthesis (anabolism) often closely parallel pathways of biodegradation (catabolism). Thus, catabolism begins with hydrolytic breakdown of polymeric molecules the resulting monomers are then cleaved into small two- and three-carbon fragments. Biosynthesis begins with formation of monomeric units from small pieces followed by assembly of the monomers into polymers. The mechanisms of the individual reactions of biosynthesis and biodegradation are also often closely parallel. However, in most instances, there are clear-cut differences. A first principle of biosynthesis is that biosynthetic pathways, although related to catabolic pathways, differ from them in distinct ways and are often catalyzed by completely different sets of enzymes. 

The six-carbon chain of ManNAc 6-P can be extended by three carbon atoms using an aldol-type condensation with a three-carbon fragment from PEP (Eq. 20-7, step c) to give N-acetylneuraminic acid (sialic acid).48 Tire nine-carbon chain of this molecule can cyclize to form a pair of anomers with 6-membered rings as shown in Eq. 20-7. In a similar manner, arabi-nose 5-P is converted to the 8-carbon 3-deoxy-D-manno-octulosonic acid (KDO) (Fig. 4-15), a component of the lipopolysaccharide of gram-negative bacteria (Fig. 8-30), and D-Erythrose 4-P is converted to 3-deoxy-D-arafrmo-heptulosonate 7-P, the first metabolite in the shikimate pathway of aromatic synthesis (Fig. 25-1).48a The arabinose-P used for KDO synthesis is formed by isomerization of D-ribulose 5-P from the pentose phosphate pathway, and erythrose 4-P arises from the same pathway. 

In several of the previously described methods the anion of the three-carbon fragments was added to an a-amino aldehyde to construct a C—C bond between the C3 and C4 atoms of the 1-hydroxyethylene isostere. However, Sakurai et al.[27l used an add chloride instead of an a-amino aldehyde. They synthesized 6-phthalimido-y-oxo esters by a palladium-catalyzed reaction between acid chlorides and organozinc reagents derived from p-iodo esters. Then, the oxo esters were converted into the y-lactone precursors. 

The rapid spontaneous mutarotation of glucose-6-phosphate has been shown to result from an intramolecular catalysis of the reaction by the phosphate group at carbon 6 (81). The cleavage of glucose into three carbon fragments, which is essentially a reversal of the aldol condensation reaction, requires the ketohexose as substrate. The necessary isomerization reaction to form the ketohexose then uses the open-chain form intermediate of the mutarotation reaction. Salas et al. (80) have speculated that the enhanced mutarotation of glucose-6-phosphate may thus have been the key requirement which led to the evolution of the phosphorolytic pathway for glucose metabolism. 

Because one glucose molecule yields two three-carbon fragments, each of which goes on to become pyruvate, there is a net synthesis of two ATP molecules for each glucose molecule consumed. 

Iminopropadienones are highly reactive species that have been used as three-carbon fragments in the synthesis of 1,4-diazepines <2002JOC2619>. Aryl- and neopentyl-substituted iminopropadienone derivatives are stable at 25 °C and the latter, 99, reacted with iV,iV -dimethyl-l,2-diaminoethane to afford a 55% yield of the l,4-diazepin-5-one 100, a compound that partially tautomerized to the enamide 101 upon Kugelrohr distillation. 

Acetylated derivatives of Baylis-Hillman adducts derived from ethyl acrylate and aromatic and heteroaromatic aldehydes are synthetically accessible three-carbon fragments that readily react with phenylenediamine under the influence of base to provide l,4-benzodiazepin-2-ones in good overall yield, as depicted in Scheme 71 <2006S4205>. 

Resin-bound 7-keto sulfones, prepared in a straightforward, three-step process comprising alkylation of a resin-bound sulfinate salt, alkylation of a sulfone-supported anion with an epoxide, and Jones oxidation of the 7-hydroxy sulfone, provided a source of structurally diverse three-carbon fragments <2004JC0928>. Reaction with a phenylenediamine to give the 1,5-benzodiazepine presumably occurs via initial imine formation followed by expulsion of the resin-bound sulfone, which acts as a traceless linker (Scheme 73). Yields for this process are a modest 10-38%. 

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