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A strategy for the syntheses of pyrrolo [2,1-a] isoquinolines and indolizinoindolones via a Brønsted acid and Lewis acid co-promoted cascade reaction has been developed. The strategy was exemplified in the total synthesis of Erysotramidine.

This article is an account of our efforts over the last decade to functionalize phenols and anilines at any position and to use these compounds to generate substituted aromatic systems and advanced unsaturated cyclohexanone moieties, enabling the rapid formation of complex structures. Total syntheses of numerous natural products involving such intermediates were achieved.1 Introduction2 ortho-Functionalization of Phenols and Aniline Derivatives Mediated by Iodanes (III) and Synthesis of Panacene2.1 Cross-Coupling with Aniline Derivatives2.2 Dearomative Cycloaddition of Arenes and Heteroarenes2.3 Total Synthesis of Panacene3 meta-Functionalization of Aniline Derivatives and Synthesis of Erysotramidine3.1 meta-Functionalization of Aniline Derivatives3.2 Total Synthesis of Erysotramidine4 para-Functionalization of Phenols and Applications in Total Synthesis4.1 Bimolecular Approach Mediated by Protecting Groups4.2 ipso-Rearrangement4.3 Oxidative Alkyl Shift4.4 Oxidative Prins-Pinacol Rearrangement4.5 Oxidative Prins-Type Reaction4.6 Total Synthesis of (–)-Fortucine4.7 Total Synthesis of Isostrychnine4.8 Total Synthesis of (–)-Strychnopivotine5 Development of a Functional Protecting Group

A domino process consisting of an amidation, spirocyclization, and formation of an iminium ion and electrophilic aromatic substitution of a phenylethylamine and a ketoester leads to the spirocyclic skeleton of (+)-erysotramidine, which can be further transformed into the natural alkaloid.

Oxidative amidation chemistry provides a unified route to aromatic Erythrina alkaloids through a sequence that illustrates new principles and improved conditions to effect a crucial eliminative Curtius–Schmidt rearrangement.

[reaction: see text] A general and efficient strategy to both aromatic-type and nonaromatic-type erythrinan and homoerythrinan alkaloids has been developed. This approach involves a key two-step sequence, an alkylation of a ketone with various N-substituted iodoacetamides followed by a N-acyliminium ion promoted intramolecular cyclization, and represents one of the shortest routes to erythrinan and homoerythrinan alkaloids. As the application, the formal total synthesis of (+/-)-3-demethoxyerythratidinone and the total synthesis of (+/-)-erysotramidine have been achieved, respectively.

For the selective formation of each isomer, we have tried the cyclization reaction under different conditions by changing solvent, catalyst, and temperature. How-ever, the ratio did not shift favorably for the purpose, so we con-sidered that we had better find ways to transform each isomer to proper natural products or derivatives. It was envisioned that major intermediate

The alkaloids present in the seeds or foliage of six Erythrina species, E. americana Miller, E. coralloides A. DC., E. lepthoriza A. DC., E. mexicana Krukoff, E. oaxacana Krukoff and E. sousae Krukoff have been screened by gas chromatography-mass spectrometry (GC/MS). The concentration of alkaloids was variable among species and organs, but highest in flowers and seeds. The composition of alkaloids in seeds, flowers, leaves and bark was different among species. The alkaloids of the dienoid type were most abundant than alkenoid series. Erysotrine, erythraline and erythratidine were detected in E. lepthoriza, E. mexicana, E. oaxacana and E. sousae. 11-hydroxylated, 11-methoxylated and y 8-oxo-alkaloids (crystamidine and erysotramidine) and erybidine, not described previously in these species were also detected. Erysotrine-N-oxide has been isolated from E. leptorhiza for the first time. The erythroidines were the main alkaloids detected in E. americana and E. coralloides together with minor alkaloids which support their taxonomic differences.

Conversion of a simple furan into the intact erythrinane skeleton in one synthetic operation has been accomplished. The one-pot reaction sequence begins with singlet oxygen photooxygenation of the furan and proceeds via a 2-pyrrolidinone formation, cyclization of the pendant aldehyde moiety and an N-acyliminium ion formation and terminates with a Pictet-Spengler-type aromatic substitution. The method has been used to achieve a rapid and highly effective formal synthesis of erysotramidine.

The condensation of (I) with (II) yields (III) and (IV) which can be used as intermediates for the synthesis of erysotramidine precursor (VI) and iso-13-demethoxyerythratidinone (IX).

A new Erythrina alkaloid, 10-hydroxy-11-oxoerysotrine (1), has been isolated from the flowers of Erythrina herbacea together with five known compounds: erytharbine (2), 10,11-dioxoerysotrine (3), erythrartine (4), erysotramidine (5) and erysotrine-N-oxide (6). The structure of the new compound was elucidated on the basis of its spectral data, including 2-D NMR and mass (MS) spectra. The new compound is a rare C-10 oxygenated Erythrina alkaloid. The antioxidant activities of the isolated compounds 1–6 were evaluated by scavenging with peroxynitrite.

A new asymmetric total synthesis of the erythrinan alkaloid erysotramidine is described, which uses chiral base desymmetrisation, N-acyliminium addition, and 6-exo-trig radical cyclisation as the key steps.

An NBS-promoted intramolecular electrophilic aromatic substitution reaction of a hexahydroindolinone derivative was used to assemble the tetracyclic core of the erythrinane skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine in three additional steps. The cyclization reaction is also successful using variously substituted aryl and furanyl bicyclic lactams under acidic conditions. [reaction: see text]

Oxidation of an erythrinan akaloid erysotramidine (4) with CAN in AcOH-MeCN gave, in moderate yield, the 11β-acetoxy derivative (5b), which was transformed into erythrartine (8). Its O-acetate (O-acetylerythrartine) was not identical with erythrascine in the 1 H-nmr spectra, presenting an ambiguity on the reported structure of erythrascine

A simple synthetic route to (±)-erysotramidine (1), an oxo-erythrinan alkaloid, including the novel ring cleavage of the aza-tricyclo[3.2.0.0] compound (6) with phenylselenyl chloride is reported.