Tetracycline is a broad spectrum antibiotic that is active against penicillin-resistant Gram-positiv — Analytical Chemistry Chemistry Question
Synthesis of Tetracycline
Tetracycline is a broad spectrum antibiotic that is active against penicillin-resistant Gram-positive bacterial organisms. The first synthesis of a tetracycline was reported by R. B. Woodward (Harvard University) and the Pfizer Pharmaceutical Company in 1962. Three of the four rings were synthesized by the following steps.
[VISUAL]
Hints: (1) the conversion of E to F involves only one methanol reactant; (2) compounds A, B, C, D, and E have proton NMR spectra with two hydrogen signals above 7.8 δ; these absorptions are not present in compounds G, H, and I.
Note: psi = pound per square inch; 1 psi equals 6,894.76 Pascals.
Complete the reactions and identify the structures of compounds A–I.
Model Answer
The structures of compounds A–I are as follows:
- A: Obtained from the starting material (3-methoxy-isobenzofuran-1(3H)-one derivative / methyl 2-(dimethoxymethyl-6-methoxybenzoate derivative) via Claisen condensation with methyl acetate (CH3COOCH3) under basic conditions, yielding a beta-keto ester derivative with a methyl ester and a methoxy group.
- B: The enolate anion (carbanion) formed by deprotonating the active methylene carbon of A with base.
- C: The alkylation product obtained by reacting anion B with methyl bromoacetate (BrCH2COOCH3) via nucleophilic substitution (SN2).
- D: The Michael addition product formed by reacting C with methyl acrylate (CH2=CHCOOCH3) under basic conditions.
- E: Formed by acidic hydrolysis (H3O+, reflux) of all three methyl ester groups of D to carboxylic acids, followed by decarboxylation of the beta-keto acid, yielding a dicarboxylic acid derivative containing a ketone.
- F: Formed by selective mono-esterification of E with one equivalent of methanol (CH3OH) in the presence of an acid catalyst (H+), esterifying the less sterically hindered carboxylic acid group.
- G: Formed by catalytic hydrogenation/hydrogenolysis (H2, Pd catalyst, 200 psi) of F, which reduces the ketone carbonyl group completely to a methylene (-CH2-) group.
- H: Formed by electrophilic aromatic substitution (chlorination) of G with chlorine (Cl2), resulting in the introduction of a chlorine atom onto the aromatic ring (ortho/para to the methoxy group) with the loss of HCl.
- I: Formed by intramolecular Friedel-Crafts acylation of H in HF (with loss of H2O), where the remaining carboxylic acid group acylates the chlorinated benzene ring to close the third ring of the tetracycline core, yielding a tricyclic ketone intermediate.