Formation of 3,4‐Diarylpyrrole‐ and Pyrrolocoumarin Core of Natural Marine Products via Barton–Zard Reaction and Selective O‐Demethylation

Abstract

A metal-free approach to 3,4-diarylpyrrole-2-carboxylate and pyrrolocoumarin cores of lamellarins and related natural products based on Barton-Zard reaction of nitrostilbenes with ethyl isocyanoacetate was developed. In the case of diarylpyrrole-2-carboxylates with a 3-(o-methoxyphenyl)[a] N. Scheme 1. Formation of the lactone fragment. Results and Discussion An Approach to 3,4-Diarylpyrrole CoreSurprisingly, a Barton-Zard reaction [21] (that is, base-catalyzed reaction of nitroalkenes with alkyl isocyanoacetate) has not yet been reported for synthesis of the pyrrole core of lamellarins and related compounds, [22] though such reaction with 1,2-diaryl-1-nitroethylenes should be a straightforward way of accessing 3,4-diarylpyrrole-2-carboxylates as key structural fragments of the lamellarins, ningalins, and lukianols. Scheme 2. Synthesis of Lamellarin Q Et ester. i: CNCH 2 COOEt, EtOH, K 2 CO 3 , 87 %; ii: BBr 3 (3 equiv.), CH 2 Cl 2 , 0°C, 85 %; iii: BBr 3 (2 equiv.), CH 2 Cl 2 , 0°C, 63 %; iv: 4-HOC 6 H 4 CHO, MeOH, MeNH 2 ·HCl, NaHCO 3 ; v: CNCH 2 COOEt, EtOH, K 2 CO 3 . EurJOCEuropean Journal of Organic Chemistry demethylated under the action of BBr 3 (3 equiv.) to afford lamellarin Q Et ester (Scheme 2):Noteworthy, the reaction in the presence of 2 equiv. of BBr 3[24] demonstrated a pronounced selectivity: it produced a mixture of partially demethylated products 2b and 2c in ca. 1:4 ratio. The structure of a minor product (2b) was confirmed by its alternative synthesis from 2-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1-nitroethene 1b (Scheme 2) (the latter was, in turn, prepared by condensation of 4-methoxyphenylnitromethane and 4-hydroxybenzaldehyde).Demethylation of methyl 3,4-bis(4-methoxyphenyl)pyrrole-2carboxylate 3a with excess BBr 3 (3 equiv.) furnished lamellarin Q (Scheme 3, Figure 2): Scheme 3. Synthesis of Lamellarin Q. i: BBr 3 (3 equiv.), CH 2 Cl 2 , 0°C, 84 %; ii: MeONa, reflux, 84 %; iii: CNCH 2 COOEt, MeOH, K 2 CO 3 , 89 %.Figure 2. Molecular structure of Lamellarin Q·MeCN (50 % ellipsoids).

Synthesis of lamellarin R, lukianol A, lamellarin O and their analogues

“…Recently, Samet and coworkers 17 have reported a metal-free synthesis of ethyl-3,4-diarylpyrrole-2-carboxylate (1) via Barton-Zard reaction 18 of nitrostilbene (2) with ethyl isocyanoacetate (Scheme 1), and subsequently applied it to the synthesis of lamellarin Q. To further demonstrate the usefulness of this Barton-Zard reaction to the preparation of another lamellarin type III alkaloids, here we report the modular synthesis of lamellarin R, lukianol A and lamellarin O, utilizing the Barton-Zard reaction to construct the pyrrole core.…”

Toward “E‐Ring‐Free” Lamellarin Analogues: Synthesis and Preliminary Biological Evaluation

“…Other commercially available solvents and reagents were used without further purification. Pyridinium ylides 1 and 1 a , [25] nitrostilbenes 2 and 2 a – 2 c [24a,26] have been synthesized according to the described methods. Compounds 5 a – 5 c were prepared according to the published procedure [21] .…”

An Overview of the Synthesis of 3,4-Fused Pyrrolocoumarins of Biological Interest

“…Silyanova et al presented the synthesis of chromeno[3,4- b ]pyrrol-4(3 H )-one derivatives in 71–83% yield via selective O -demethylation of 3-(2-methoxyphenyl)pyrrole derivatives 270a – l and treatment of the resulting phenolic derivatives 271a – l with ethanolic NaOH at room temperature [ 135 ]. Compounds 270a – l were prepared by the Barton–Zard reaction of nitrostilbenes 269a – l with ethyl isocyanoacetate ( Scheme 72 ).…”