Pyrrolizidine alkaloids and their unnatural analogues occupy the important place in organic chemistr — Organic Chemistry Chemistry Question
Pyrrolizidine alkaloids
Pyrrolizidine alkaloids and their unnatural analogues occupy the important place in organic chemistry due to a broad variety of physiological activities. Polyhydroxylated pyrrolizidines form a sub-class of these alkaloids, members of which are often referred to as aza-sugars (or imino sugars) and inhibit various glycosidases that can be useful for the treatment of diabetes, influenza, HIV and other diseases. The synthesis of dihydroxypyrrolizidine alkaloid, (±)-turneforcidine, is given in the Scheme 1. In this scheme E is an unstable intermediate which spontaneously undergoes the Claisen rearrangement producing F.
[VISUAL]
Epimer of turneforcidine at C(7) atom, (±)-platynecine, was synthesized by the reaction sequence given in Scheme 2. It is noteworthing that K is the product of [2+2]-cycloaddition.
[VISUAL]
Decipher these schemes. Write down the structural formulae of compounds A – M as well as of (±)-platynecine.
Model Answer
The molecular formula of compound B is a sum of molecular formulae of three reactants without 2 HCl. It is possible to conclude that A is the product of addition of ethyl ester of glycine to ethyl acrylate, and B is the product of acylation of A with ethyl chloroformate.
During next two steps molecule of B lost 5 carbon atoms, 10 hydrogen atoms and 3 oxygen atoms. It corresponds to the removal of ethoxy group, ethyl group and CO2 molecule. The transformation of B to C is induced by EtONa. It is possible to suppose that this step is the intramolecular Claisen condensation furnishing 3-oxopyrrolidine-4-carboxylic acid (removal of ethanol). Its treatment with 10% sulfuric acid leads to hydrolysis of ester group (but not the less reactive carbamate) and decarboxylation. This supposition is consistent with the demand of synthesis of pyrrolizidine alkaloid consisting of two five-membered rings.
The intermediate E undergoes Claisen rearrangement, i.e., it contains the fragment of allyl vinyl ether. This fragment can be prepared from the allyl alcohol and the ketone by the acid-catalyzed attack of the alcohol onto the carbonyl carbon affording an enol ether. The Claisen rearrangement produces pyrrolidone containing the substituted allyl group connected to C(2) or C(4) atom (depending on the regiochemistry of the enol moiety formation). Even we do not know that the enolization with the participation of C(2) atom is more preferable, we can conclude that the allyl group is connected with the C(2) atom from the necessity to prepare pyrrolizidine scaffold. It will be impossible (using the transformations given in the Scheme 1) if the allyl group is connected with the C(4) atom.
The reduction of ketone group with NaBH4 produces the corresponding alcohol, alkylation of which with benzyl bromide gives rise to H. Its molecular formula coincides with the formula given in the Problem. Next step is the hydrolysis of carbamate (otherwise, it is impossible to form the second five-membered ring). Attack of electrophilic phenylsulfanyl chloride on the C=C bond is accompanied by the nucleophilic attack of the pyrrolidine nitrogen on the formed sulfonium ion furnishing pyrrolizidine system. The removal of the phenylsulfanyl group and the hydrogenolysis of Bn-O bonds accomplish the synthesis of (±)-turneforcidine. The relative stereochemistry of all stereocenters can be unambiguously deduced from the given stereochemistry for (±)-turneforcidine.
The analysis of the scheme 2 shows that molecular formula of K is a sum of molecular formulae of reacting compounds without HCl. K is the product of [2+2]-cycloaddition. Evidently, the C=C bond of the pyrroline is involved in this process. The second partner (4-chlorobutyroyl chloride) has C=O bond. However, isomeric products of two possible [2+2]-cycloadditions between these moieties fail to form pyrrolizidine framework. However, elimination of HCl from acyl chloride can produce ketene which is able to form [2+2]-cycloadduct with pyrroline. Accounting for further formation of the pyrrolizidine scaffold, the regiochemistry of the cycloaddition is unambiguous.
The transformation of L to M is the hydrogenolysis of the Bn–O bond followed by CO2 elimination from the formed carbamic acid. During this step the NH moiety is formed. As the last step of the platynecine synthesis is the reduction, the NH moiety should cyclize affording pyrrolizidine immediately after formation. Platynecine is a diastereomer of turneforcidine, i.e., platynecine contains the same substituents. This allows for concluding that the last step is the reduction of ester function producing two alcohols. In other words, the transformation of K to L is the oxidation of cyclobutanone fragment to the corresponding lactone. This reaction is known as the Baeyer-Villiger oxidation.