In nature, there are many known species of the ladybug family (Coccinellidae). Besides their cutenes — Organic Chemistry Chemistry Question
Life of Ladybug
In nature, there are many known species of the ladybug family (Coccinellidae). Besides their cuteness, they play a beneficial ecological role in controlling populations of some harmful insects. When molested or disturbed, they emit droplets of a fluid from their joints. This process known as “reflex bleeding”, serves as an efficient deterrent. This fluid was isolated, characterized and termed as coccinelline. The structure of coccinelline is given below:
[VISUAL]
In laboratory synthesis of coccinelline, very common and readily available starting compounds are chosen (See the scheme below.)
[VISUAL]
The reaction between dimethyl malonate and acrolein in the presence of sodium methoxide yields compound A. Subsequently, it is heated in basic solution followed by esterification with methanol under acidic condition to afford compound B. The 13C-NMR spectrum of compound B shows two characteristic signals at around 170 and 200 ppm. Then, the compound B is treated with ethane-1,2-diol under slightly acidic condition to give compound C. The signal of compound B at around 200 ppm disappears in the 13C-NMR spectrum of compound C. Compound C undergoes a self condensation reaction in the presence of NaH to yield compound D. Decarboxylation reaction of compound D affords compound E. In the next step, compound E is first reacted with ammonium acetate followed by reduction with sodium cyanoborohydride. In this step, compound F is formed via the reductive amination of the compound E.
Draw the structures of the compounds A, B, C, D, E and F.
Model Answer
The structures of the compounds A, B, C, D, E and F are:
- Compound A: formed by the conjugate addition of dimethyl malonate to acrolein.
- Compound B: formed by basic hydrolysis of A, heating, and subsequent acidic esterification with methanol. It shows two characteristic 13C-NMR signals at around 170 ppm (ester) and 200 ppm (ketone).
- Compound C: formed by protecting the ketone of B as an acetal using ethane-1,2-diol (the ketone signal at 200 ppm disappears).
- Compound D (C15H24O7): formed by self-condensation of C in the presence of NaH.
- Compound E: formed by basic hydrolysis and heating of D to undergo decarboxylation.
- Compound F (C13H25NO4): formed by reductive amination of E with ammonium acetate and sodium cyanoborohydride.
In the next part of synthesis, compound F is first deprotected at pH 1 and, then, the pH is adjusted to 5 followed by the addition of acetone dicarboxylic ester which can easily be enolizable. As a result of this step, the tricyclic compound G is isolated as the sole product.
Draw the structure of compound G. Propose a plausible mechanism for the formation of compound G.
(Hint: After deprotection step, iminium ion is formed and reacted with enolizable acetone dicarboxylic ester.)
Model Answer
Deprotection of compound F under acidic conditions (pH 1) hydrolyzes the acetal back to a ketone, which undergoes intramolecular condensation with the amine to form an iminium ion. When the pH is adjusted to 5, the enolizable acetone dicarboxylic ester undergoes nucleophilic addition to the iminium ion. Subsequent intramolecular cyclization steps lead to the formation of the tricyclic compound G (as shown in the detailed step-by-step mechanism in the solution key, where the deprotected F reacts with dimethyl 3-oxopentanedioate to form G).
The final part of synthesis involves the decarboxylation of compound G under basic condition to afford compound H. The 13C-NMR spectrum of compound H shows the characteristic signal at around 200 ppm. The reaction of compound H with methylene triphenylphosphorane yields compound I which is subsequently hydrogenated to afford precoccinelline. In the final step, precoccinelline is oxidized with m-chloroperbenzoic acid (m-CPBA) to get coccinelline.
F + [VISUAL] pH 1 to pH 5 G OH-, H2O heat H Ph3P=CH2 I H2, Pd [VISUAL] Precoccinelline
Draw the structures of G, H and I.
Model Answer
The structures are as follows:
- Compound G: Tricyclic compound containing two carbomethoxy (ester) groups and a ketone carbonyl.
- Compound H: Obtained by basic hydrolysis and decarboxylation of G, resulting in a tricyclic ketone (with a characteristic 13C-NMR signal at around 200 ppm).
- Compound I: Obtained by Wittig reaction of the ketone in H with methylene triphenylphosphorane, converting the carbonyl group to an exocyclic carbon-carbon double bond (=CH2).
Precoccinelline is obtained by hydrogenation of the double bond in I, and coccinelline is obtained by oxidation of precoccinelline with m-CPBA to form the N-oxide.