Aldol reactions biosynthesis

V. Aldol Reactions of Heterocyclic Enamines and Their Importance for the Biosynthesis of Alkaloids... 

Acyclic stereocontrol has been a striking concern in modern organic chemistry, and a number of useful methods have been developed for stereoregulated synthesis of conformationally nonrigid complex molecules such as macrolide and polyether antibiotics. Special attention has therefore been paid to the aldol reaction because it constitutes one of the fundamental bond constructions in biosynthesis. 

Both the aldol and reverse aldol reactions are encountered in carbohydrate metabolic pathways in biochemistry (see Chapter 15). In fact, one reversible transformation can be utilized in either carbohydrate biosynthesis or carbohydrate degradation, according to a cell s particular requirement. o-Fructose 1,6-diphosphate is produced during carbohydrate biosynthesis by an aldol reaction between dihydroxyacetone phosphate, which acts as the enolate anion nucleophile, and o-glyceraldehyde 3-phosphate, which acts as the carbonyl electrophile these two starting materials are also interconvertible through keto-enol tautomerism, as seen earlier (see Section 10.1). The biosynthetic reaction may be simplihed mechanistically as a standard mixed aldol reaction, where the nature of the substrates and their mode of coupling are dictated by the enzyme. The enzyme is actually called aldolase. 

In Box 10.4 we saw that an aldol-like reaction could be used to rationalize the biochemical conversion of dihydroxyacetone phosphate (nucleophile) and glyceraldehyde 3-phosphate (electrophile) into fructose 1,6-diphosphate by the enzyme aldolase during carbohydrate biosynthesis. The reverse reaction, used in the glycolytic pathway for carbohydrate metabolism, was formulated as a reverse aldol reaction. 

Inspired by the biosynthesis of carbohydrates we envisaged a direct de novo synthesis of carbohydrate derivatives by using the DHA-equivalent 4 in a C3+Cn-sirategy. As can be seen from the retrosynthetic analysis, the desired building blocks 5 should be prepared from the dioxanone (4) and an aldehyde component 6 in an organocatalytic aldol reaction... 

Microbes and plants synthesize aromatic compounds to meet their needs of aromatic amino acids (L-Phe, L-Tyr and L-Trp) and vitamins. The biosynthesis of these aromatics [69] starts with the aldol reaction of D-erythrose-4-phosphate (E4P) and phosphoenolpyruvate (PEP), which are both derived from glucose via the central metabolism, into DAHP (see Fig. 8.13). DAHP is subsequently converted, via a number of enzymatic steps, into shikimate (SA) and eventually into chorismate (CHA, see later), which is the common intermediate in the biosynthesis of the aromatic amino acids [70] and vitamins. 

In the biosynthesis of bacterial lipopolysaccharides 3-deoxy-D-manno-2-octulosonate 8-phosphate (KDO 8-P) synthetase (EC 4.1.2.16) is involved in catalyzing the irreversible aldol reaction of... 

The starting point of the biosynthesis is -caproic acid, from which a triketo-carboxylic acid is constructed in successive polyketide steps. Olivetolic acid is formed by an intramolecular aldol reaction, its decarboxylation generates olivetol. 

An example of Claisen reaction is provided by the first step in the biosynthesis of cholesterol and terpenes, which starts from acetyl-CoA. Similar to the Claisen condensation, 2equiv of acetyl-CoA couple to acetoacetyl-CoA, which represents a biological analog of acetoacetate. Following the pattern of an aldol reaction, acetoacetyl-CoA reacts with another equivalent of acetyl-CoA as a carbon nucleophile to give p-hydroxy-p-methylglutaryl-CoA (Figure 1.20). 

In the study of biosynthesis of polyketide antibiotics. Cane and Luo applied the Evans aldol reaction to prepare a key intermediate 41 from aldehyde 40 and Evans reagent 20. °... 

In a study on the biosynthesis of the polyether antibiotic lasalocid A, a syn-selective Evans aldol reaction of 83 with methacrolein gave 84 in 95% isolated yield. In the total synthesis of the antitumor sesquiterpenoid (+)-eremantholide A, an Evans aldol reaction was used to deliver a single syn-... 

The biosynthesis of simple stilbenes has been found out, and it shared a similar biosynthetic pathway with the flavonoids. Taking resveratrol for example, it starts from a cinnamoyl-CoA unit and extended the chain with three malonyl-CoA molecules (Scheme 62.1) [105]. Then, the resveratrol structure is produced by aldol reaction with the presence of stilbene synthase. Nevertheless, the flavonoids are formed depending on chalcone synthase and Claisen reaction. 

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