A Triple Cascade Sequence as a Strategy for the Construction of the Erythrinane Skeleton

Abstract

α-Thiocarbocations generated from Pummerer reactions of several o-imido sulfoxides were intercepted by adjacent carbonyl groups to produce α-amido-substituted isobenzofurans as transient intermediates. When an olefinic tether was present, intramolecular Diels−Alder cycloaddition occurred followed by a ring-opening−elimination sequence that produced an N-acyliminium ion. Deprotonation of the iminium ion led to oxindole derivatives in good yields. When the iminium ion contained both a blocking substituent, such as a carbomethoxy group, as well as an activated aromatic π-tether, the N-acyliminium ion intermediate underwent stereoselective spirocyclization to afford cis-3,4-benzoerythrinane or homoerythrinane derivatives in good yield. The overall triple cascade sequence represents an efficient one-pot approach toward the erythrina skeleton in which the spirocyclic ABC skeleton is assembled in a single operation. The scope and limitations of the triple cascade were explored by varying both the olefinic and nucleophilic tethers. The required sulfoxide precursors for these Pummerer-induced transformations were easily synthesized starting from 2-[(ethylthio)methyl]benzoic acid. The tandem Pummerer/Diels−Alder/N-acyliminium ion cyclization was used for the synthesis of indoloisoquinoline 38. Since compound 38 was converted to 47 which, in turn, was transformed into erysotramidine (2), its preparation represents an extraordinarily facile, formal synthesis of this member of the Erythrina alkaloid family.

Stereodivergent Synthesis of Hetero-Fused Isoquinolines by Acyliminium and Metallation Methods

“…This class of intramolecular amidoalkylations, involving bond formation at the least hindered side, opposite to the substituent, has been used in the synthesis of heterocyclic systems. [6] Similar facial diastereoselectivities have been observed by Padwa [7] and Allin [8] in their synthesis of Erythrina-type alkaloids and ring-fused chiral isoindolones, respectively, via bicyclic N-acyliminium ions.…”

Asymmetric Synthesis of Crispine A: Constructing Tetrahydroisoquinoline Scaffolds Using Pummerer Cyclizations

“…To overcome the unforeseen difficulty in C–C bond formation for the construction of the six‐membered ring, a Pummerer type cyclization was attempted. Pummerer type transformations have widespread applications in heterocyclic syntheses, especially in the production of various alkaloid skeletons 20e,20f. The Pummerer cyclization reaction proceeds through an initially generated thionium ion which is trapped by a nucleophile present in the reaction medium.…”

Linked Pummerer-Mannich Ion Cyclizations for Heterocyclic Chemistry

“…15 Formation of the required preassembled sulfoxide-amide (42) involved a number of straightforward steps. When treated with a Pummerer promoter, a series of events occurred which culminated in the formation of the ring system of the sulfoxide (42) with a Pummerer promoter first generates a thionium ion which then undergoes cyclization to give the desired 2-amidofuran.…”