General Strategy for the Synthesis of Antirhine Alkaloids: Divergent Total Syntheses of (±)-Antirhine, (±)-18,19-Dihydroantirhine, and Their 20-Epimers

Abstract

A general synthetic strategy for antirhine alkaloids was developed in this study. The cyanide-catalyzed imino-Stetter reaction of ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde afforded the corresponding indole-3-acetic acid derivative. Subsequent formation of the six-membered C ring followed by trans-selective installation of the two-carbon unit at C-15 provided rapid access to the key intermediate. Stereoselective installation of substituents at C-20 allowed the total syntheses of (±)-antirhine, (±)-18,19-dihydroantirhine, and their 20-epimers, all of the known natural products in the antirhine family.

Total Synthesis of Iheyamine A via the Cyanide-Catalyzed Imino-Stetter Reaction

“…Our group recently developed an efficient protocol to construct 2-substituted indole-3-acetic acid derivatives via the cyanide-catalyzed imino-Stetter reaction of aldimines derived from 2-aminocinnamic acid derivatives and aldehydes. − This protocol was successfully applied to the synthesis of symmetrical 2,2′-bisindole-3-acetic acid derivatives from unsubstituted 2-aminocinnamic acid derivatives and indole-2-carboxaldehyde derivatives . Based on this method, we envisaged that the imino-Stetter reaction could likewise be used to prepare an unsymmetrical 2,2′-indole scaffold from aldimines derived from 2-aminocinnamic acid derivatives bearing a substituent on the phenyl ring and substituted indole-2-carboxaldehyde derivatives.…”

A Stereodivergent Strategy for Total Syntheses of Antirhine Alkaloids

“…Yields refer to chromatographically and spectroscopically pure compounds, unless otherwise noted. 2-Bromo-7,12-dihydro-6 H -indolo­[2,3- a ]­quinolizin-5-ium trifluoromethanesulfonate ( 5b ) was prepared by the reported procedures . Other reagents were purchased from chemical suppliers and used without further purification.…”

“…2-Bromo-7,12-dihydro-6Hindolo [2,3-a]quinolizin-5-ium trifluoromethanesulfonate (5b) was prepared by the reported procedures. 8 Other reagents were purchased from chemical suppliers and used without further purification. 1 H and 13 C NMR spectra were recorded on 500 and 125 MHz spectrometers, respectively.…”

“…Based on this idea, very recently, our group reported the stereodivergent total syntheses of antirhine ( 1 ) and its 20-epimer ( 2 ) (Scheme ). The cyanide-catalyzed imino-Stetter reaction of the aldimine derived from ethyl 2-aminocinnamate ( 3 ) and 4-bromopyridine-2-carboxaldehyde ( 4b ) afforded an indole-3-acetate derivative bearing a pyridyl ring at the 2-position. Subsequent six-membered C-ring formation provided indoloquinolizidinium intermediate 5b .…”

“…Although this new approach allowed the stereodivergent total syntheses of antirhine (1) and its congeners, a few issues remained to be resolved in our previous synthesis. 8 (1) During the incorporation of the homoallylic alcohol side-chain from intermediate 5b through the reactions with 1,3-dicarbonyl compounds, an unexpected formation of the 1,4-dihydropyridinyl scaffolds rather than the corresponding pyridinium salts was encountered, which rendered the control of the stereochemistry between the C-3 and C-15 centers in indoloquinolizidine 6 challenging. (2) In the preparation antirhine (1) via hydroxymethylation with methoxymethyl (MOM) chloride, the final demethylation was problematic leading to a significant decrease in the yield of the desired natural product.…”