Flow Photochemistry as a Tool for the Total Synthesis of (+)-Epigalcatin

Abstract

The first total synthesis of (+)-epigalcatin was completed in a highly stereoselective manner starting from piperonal, 3,4-dimethylbenzaldehyde, and diethyl succinate. l-Prolinol was used as a chiral auxiliary. The crucial step in this procedure involves the construction of the cyclolignan framework by continuous-flow photocyclization of a chiral atropisomeric 1,2-bisbenzylidenesuccinate amide ester.

Unique cyclolignan’s architecture obtained via acid catalyzed cyclization/intramolecular Friedel-Crafts tandem reaction

“…Melting points were determined on an Electrothermal, Model IA 9200 apparatus and are uncorrected. 1 H and 13 C NMR spectra were recorded on a Bruker AVANCE 500 spectrometer. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard in CDCl3 solution.…”

“…10 We found that L-prolinol is an excellent chiral auxiliary 11 and used for the formal synthesis of PPT 12 and the total synthesis of (+)-epigalcatin. 13 We also studied the regioselectivity in the photocyclization of cyclolignan precursors 14 and we used the bis-benzylidenesuccinyl platform as a photolabile protecting group for secondary amines. 15 Although the photocyclization of chiral bis-benzylidenesuccinates is relatively better studied, it is also possible to obtain cyclolignans via acid catalyzed cyclization, as shown in Charlton's total synthesis of (+)-lyoniresinol dimethyl ether, in which (-)-ephedrine was used as a chiral auxiliary and triflic acid (TfOH) as the catalyst.…”

“…J ≈ 6 Hz, 1H), 1.96-1.91 (br q, J ≈ 6 Hz, 1H), 1.76 -1.58 (m, 2H) 13. C NMR (125 MHz) δ: 168.6, 167.3, 153.5, 153.4, 145.5, 141.6, 140.6, 140.0, 129.4, 128.9, 127.6, 125.0, 108.7, 107.9, 73.7, 61.1, 61.1, 60.0, 56.6, 56.4, 48.4, 34.8, 22.7.…”

A tribute to Professor Zbigniew Czarnocki

“…This was proven by further synthesis of another cyclolignan (+)-epigalcatin. 20 1R,2R-cis-podophyllic aldehyde, an important intermediate during the synthesis of (-)-podophyllotoxin, was converted to the first known heterodimer of podophyllotoxin and benzothiazole. This compound was much more active against the majority of the tested tumor cell lines than podophyllotoxin itself.…”

Advances in the Synthesis of Lignan Natural Products

“…Czarnocki and coworkers reported in 2018 the total synthesis of (+)-epigalcatin using a photocyclization process under continuous flow UV irradiation conditions (Scheme 24) [85]. Diester 134 was condensed with aldehyde 120 at basic conditions, affording E , E -bisbenzylidenesuccinic acid 135 .…”