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Construction Mechanismsin Natural Product Biosynthesis

Ahmad NajibFaculty of Pharmacy

Moslem University of Indonesia

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Aldol and Claisen Reactions

Imine Formation &MannichReaction

Amino Acids & Transamination

Decarboxylation Reactions

Oxidation &Reduction Reactions

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Aldol and Claisen Reactions

  • Reactions both achieve carbon–carbon bond formation; in typical base-catalysed

  • Chemical reactions, this depends upon the generation of a resonance-stabilized enolate anion from a suitable carbonyl system

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  • Claisen reactions involving acetyl-CoA are made even more favourable by first converting acetyl-CoAinto malonyl-CoAby a carboxylation reaction catalysed by the three-component enzyme acetyl-CoAcarboxylase.

  • The reaction requires CO2, ATP and the coenzyme biotin

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Result of Reaction

  • No acylatedmalonic acid derivatives

    are produced

  • The carboxyl group introduced into malonyl-CoAis simultaneously lost by a decarboxylationreaction during the Claisen condensation

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Analogy the chemical Claisen condensation using the enolateanion from diethyl malonate

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Both the reverse aldol and reverse Claisen reactionsmay be encountered in the modification of natural productmolecules.

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Imine Formation and the Mannich Reaction

  • Formation of C–N bonds is frequently achieved by condensation reactions between amines and aldehydesor

  • Ketones. A typical nucleophilic addition is followed by elimination of water to give an imine or Schiff base

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Of almost equal importance is the reversal of this process, i.e. the hydrolysis of imines to amines & aldehydes/ketones

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  • The imine so produced, or more likely its protonated form the iminiumcation, can then act as an electrophile in a Mannichreaction

  • The nucleophile might be provided by an enolate anion, or in many examples by a suitably activated centre in an aromatic ring system

  • The Mannich reaction throughout alkaloid, combination of an amine (primary/secondary), aldehyde/ketone, &nucleophilic carbon

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  • Little different fromnucleophilic addition to a carbonyl group. Indeed, the imine/iminiumcation is merely acting as the nitrogen analogue of a carbonyl/protonated carbonyl.

  • To take this analogy further, protons on carbon adjacent to an imine group will be acidic, as are those α to a carbonyl group, and the isomerization of an imine to the enamine shown

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Analogous to keto–enol tautomerism. Just as two carbonyl compounds can react via an aldol reaction, so can two imine systems; and this is indicated

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Amino Acids &Transamination

  • The synthesis of amino acids depends upon the amination of the Krebs cycle intermediate 2-oxoglutaric acid to glutamic acid, a process of reductive amination

  • The reaction involves imine formation and subsequent reduction. The reverse reaction is also important in amino acid catabolism.

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  • Glutamic acid can then participate in the formation of other amino acids via transamination, the exchange of the amino group from an amino acid to a keto acid. This provides the most common process for the introduction of nitrogen into amino acids, and for the removal of nitrogen from them.

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  • The reaction is catalysed by a transaminase enzyme using the coenzyme pyridoxal phosphate (PLP) & features an imine intermediate (aldimine) with the aldehyde group of PLP

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Decarboxylation Reactions

  • Many pathways to natural products involve steps which remove portions of the carbon skeleton.

  • Although two ormore carbon atoms may be cleaved off via the reverse aldol or reverse Claisen reactions

  • The most common degradative modification is loss of one carbon atom by a decarboxylation reaction.

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  • Decarboxylation is a particular feature of the biosynthetic utilization of amino acids

  • It has already been indicated that several of the basic building blocks (e.g. C6O2N and indole.C2N)

  • Derived from an amino acid via loss of the carboxyl group

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Oxidation & Reduction Reactions

  • Dehydrogenases

  • Oxidases

  • Monooxygenases

  • Diooxygenases

  • Amine Oxidases

  • Baeyer–Villiger Monooxygenases

  • Phenolic Oxidative Coupling

  • Halogenation Reactions

  • Glycosylation Reactions

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  • Dehydrogenases remove two hydrogen atoms from the substrate, passing them to a suitable coenzyme acceptor.

  • The coenzyme system involved can generally be related to the functional group being oxidized in the substrate.

  • Thus if the oxidation process is then a pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+) or nicotinamide adenine dinucleotide phosphate (NADP+), tends to be utilized as hydrogen acceptor.

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One hydrogen from the substrate (that bonded tocarbon) is transferred as hydride to the coenzyme and theother (as a proton) is passed to the medium

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  • Oxidases also remove hydrogen from a substrate, but pass these atoms to molecular oxygen or to hydrogen peroxide, in both cases forming water. Oxidases using hydrogen peroxide are termed peroxidases.

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  • With monooxygenases, the second oxygen atom from O2 is reduced to water by an appropriate hydrogen donor, e.g. NADH, NADPH, or ascorbic acid(vitamin C). In this respect they may also be considered to behave as oxidases, and the term ‘mixed-function oxidase’ is also used for these enzymes.

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  • introduce both atoms from molecular oxygen into the substrate, and are frequently involved in the cleavage of carbon–carbon bonds, including aromatic rings.

  • Cyclic peroxides (dioxetanes) have been proposed as intermediates and though evidence points against dioxetanes, they do provide a simple appreciation of the reaction outcome

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Amine Oxidases

  • In addition to the oxidizing enzymes outlined above, those which transform an amine into an aldehyde, the amine oxidases, are frequently involved in metabolic pathways. These include monoamine oxidases and diamineoxidases.

  • Monoamine oxidases utilize a flavin nucleotide, typically FAD, and molecular oxygen; the transformation involves initial dehydrogenation to an imine, followed by hydrolysis to the aldehyde and ammonia