THEORETICAL PROBLEM 28 ***Antiviral antibiotic*** **Ascochlorin (antiviral antibiotic)** [VISUAL] As — Organic Chemistry Chemistry Question
Antiviral antibiotic
THEORETICAL PROBLEM 28
*Antiviral antibiotic*
Ascochlorin (antiviral antibiotic)
[VISUAL]
Ascochlorin is an antiviral antibiotic obtained from the filter cake of the fermented broth of Ascochyta viciae Libert. It has a strong inhibitory effect on viral growth in cultured cells. The absolute stereochemistry of this antibiotic was determined by X-ray analysis. Due to high biological activity, the ascochlorin family has attracted the attention of synthetic organic chemists.
Part A (Synthesis of the right side of ascochlorin)
Synthesis of cyclohexanone unit (right side of ascochlorin) starts with Diels-Alder reaction which is a [4+2] cycloaddition reaction. Reaction of 1,3-butadiene and chiral dienophile 1 gives the cycloadduct A with the desired stereochemistry of cyclohexanone unit. Basic hydrolysis of A affords the sultam 2 and the chiral carboxylic acid B. This carboxylic acid B undergoes iodolactonization reaction (initial step is the formation of an iodonium ion intermediate) to form the δ-iodolactone C. Treatment of C with DBU (non nucleophilic base) forms the compound D. Reduction of D with LiAlH4 and then hydrolysis with water produces the diol E. Selective oxidation of E with pyridinium chlorochromate (PCC) leads to the product F. Subsequent protection of the hydroxy group with (CH3)3SiCl produces the compound G.
[VISUAL]
Besides [4+2] cycloaddition reaction, the compound 1 can also undergo [2+2] cycloaddition reactions. For example, the dienophile 1 undergoes a cycloaddition reaction with ketene (general formula, R2C=C=O). When the dienophile 1 is reacted with 2,2-dichloroacetyl chloride (ketene equivalent) in the presence of a base, an isomeric mixture of H and I is formed.
[VISUAL]
Part B (Synthesis of the left side of ascochlorin)
In order to synthesize the left side of the molecule (Part B), the aromatic compound J is used as starting material (PG is a protecting group for OH). Reaction of J with strong base (butyllithium, BuLi) forms the lithiated compound K. Treatment of this intermediate with copper(I) iodide and then with epoxide gives compound L. Reaction of this compound with thionyl chloride (SOCl2) produces compound M. In order to combine part A and part B, Wittig reaction is planned. For this purpose compound M is reacted with triphenylphosphine (PPh3) and then the product of this reaction is treated with BuLi to get the intermediate Wittig reactant N. Finally coupling is achieved by reaction of N with aldehyde G, which yields O, the main skeleton of ascochlorine. In order to remove (CH3)3Si group, O is treated with dilute acid solution which gives compound P. The ascochlorine synthesis is completed by five more steps.
[VISUAL]
Draw the structures of compounds A, B, C, D, E, and F with the correct stereochemistry.
Model Answer
A: [Structure of the cycloadduct from 1,3-butadiene and chiral sultam-dienophile 1]
B: [Structure of chiral cyclohexene carboxylic acid]
C: [Structure of the δ-iodolactone intermediate (C9H13IO2)]
D: [Structure of the bicyclic lactone with double bond (C9H12O2)]
E: [Structure of the diol (C9H16O2)]
F: [Structure of the hydroxy aldehyde/keto-alcohol (C9H14O2)]
(Skeletal structures are drawn in the solution containing correct stereochemistry/dashed-wedged configurations).
Draw the structure of ketene obtained in situ from 2,2-dichloroacetyl chloride.
Model Answer
Cl2C=C=O (dichloroketene)
Draw the structures of H and I.
Model Answer
H and I are diastereomeric stereoisomers resulting from the [2+2] cycloaddition of dichloroketene to the chiral dienophile 1.
Propose a mechanism for the conversion of K to L.
Model Answer
The lithiated aromatic compound K undergoes transmetalation with copper(I) iodide to form a diaryl Gilman-type cuprate intermediate: (Ar)2CuLi. This cuprate reagent then acts as a soft nucleophile, performing a regioselective ring-opening of the epoxide (methyloxirane) by attacking the less-hindered carbon. Subsequent protonation/hydrolysis with water yields the alcohol compound L.
Draw the structures of compounds M, N, O, and P.
Model Answer
M: [Aromatic compound containing a benzyl chloride subunit in place of the primary alcohol]
N: [Wittig reagent/triphenylphosphonium ylide intermediate]
O: [TMS-protected coupled olefin product forming the main skeleton of ascochlorin]
P: [Deprotected coupled olefin product (TMS group cleaved to give secondary alcohol on the cyclohexyl ring)]
The ascochlorin synthesis from compound P is completed by performing five more steps:
i. Oxidation of OH group on the cyclohexyl unit.
ii. Introduction of the methyl group to C19 (do not worry about the correct stereochemistry).
iii. Conversion of ester group on the aromatic unit to aldehyde.
iv. Selective reduction of α,β-unsaturated double bond of cyclohexenone unit.
v. Removal of protecting groups (PG) which can be achieved by using Bu4NF.
Write the reagents used for the steps i, ii, and iii.
Model Answer
i) PCC (Pyridinium chlorochromate)
ii) NaOCH3, CH3I
iii) Diisobutylaluminum hydride (DIBAL-H)