(-)-α-Noscapine is an alkaloid isolated from Papaver somniferum L. in 1817 by P. Robiquet which name — Physical Chemistry — Kinetics Chemistry Question
Antitussive “narcotine”
(-)-α-Noscapine is an alkaloid isolated from Papaver somniferum L. in 1817 by P. Robiquet which named this compound as “narcotine”. This agent demonstrates significant painkilling and antitussive activities. It is also used for treatment of cancer, stroke, anxiety, and so on. Clinically used (-)-α-noscapine is provided through extraction from natural sources or resolution of synthetic racemic compound. There are some syntheses of (±)-α-noscapine. One of them is given in the scheme below.
[VISUAL]
Decipher this scheme. Write down the structural formulae of compounds A – I if G is a tricyclic compound.
Model Answer
The analysis of the given scheme allows one to conclude that the A-to-B transformation is the iodination of A and the B-to-C transformation is the substitution of the iodine atom by methoxy group as compound C contains no iodine. The regiochemistry of iodination can be unambiguously deduced from the structure of (±)-α-noscapine (its upper fragment). Comparison of molecular formula of C and structure of initial compound leads to conclusion that the first step of the compound A formation is the aldehyde group ketalization. Therefore, we can write the structural formulae of A-C.
The acid hydrolysis of the compound C recovers the aldehyde function which reacts with amine affording the corresponding imine, the reduction of which with NaBH4 produces the secondary amine E. The repetition of the reductive alkylation of amine with aldehyde furnishes the tertiary amine F. The hydrolysis of the ketal functionality in F yields the corresponding aldehyde molecular formula of which fulfils conditions. However, in the problem it is stated that G is tricyclic compound. It is possible if acid induces aldehyde attack of the proximal aromatic ring leading to 4-hydroxy-tetrahydroisoquinoline derivative G.
Analysis of the molecular formulae of G and I shows that the transformation of G to I corresponds to the removal of hydroxy group and the introduction of iodine atom into the molecule. The structure of (±)-α-noscapine demonstrates clearly that I reacts with bromophthalide by the C(1) atom of the isoquinoline fragment. We can conclude that the G-to-H step is the ionic reduction of the benzyl alcohol moiety to CH2 group (the protonation of alcohol produces benzyl cation reaction of which with NaBH4 yields CH2 fragment) and the H-to-I step is the iodination of C(1) atom of isoquinoline core. It is known that α-iodoalkylamines exist as ionic compounds. In other words, the better presentation of the compound I is the corresponding salt but structural formula with covalent C-I bond is also considered as a right answer. The last step is the C-C bond formation producing the target (±)-α-noscapine.