Chemistry of the Hexahydropyrrolo[2,3-b]indoles:  Configuration, Conformation, Reactivity, and Applications in Synthesis

Abstract

The stereoselective formation of 2-endo-substituted hexahydropyrrolo[2,3-b]indoles from 2-substituted tryptamine derivatives, especially tryptophan, is discussed. Parallels are drawn with the formation of related heterocyclic systems, such as the hexahydrofurano[2,3-b]benzofurans, in which the thermodynamic preference of a substituent at the 2-position is also for the endo-configuration. Functionalization of tryptophan-derived hexahydropyrroloindoles at positions 2-, 3-, and 3a- is discussed with special emphasis on the 2-position, at which both radical and nucleophilic reactions take place preferentially on the endo-face of the diazabicyclo[3.3.0]octane system. The kinetic and thermodynamic preference for the 2-endo-position is considered in terms of the minimization of torsional strain, and parallels are drawn to the Woerpel model for the reactivity of analogous five-membered cyclic oxacarbenium ions. The use of the tryptophan-derived hexahydro[2,3-b]pyrroloindoles in the stereocontrolled synthesis of amino acids and alkaloids is presented.

Stereocontrolled and Versatile Total Synthesis of Bispyrrolidinoindoline Diketopiperazine Alkaloids: Structural Revision of the Fungal Isolate (+)‐Asperdimin

“…[10] Traditionally the exo and endo stereochemical notation for relative configuration of hexahydropyrroloA C H T U N G T R E N N U N G [2,3-b]indoles describes the outside or inside arrangement, respectively, of the acyl group at the C2 position relative to the cavity defined by the ring fusion. [11] This remarkable diastereoselectivy has been studied by our group by using density functional theory (DFT) calculations, which indicate that a possible mechanism of reaction involves the formation of diastereomeric C2-phenylselenyl indoline-azetidine spiranes as intermediates that undergo a concerted rearrangement to give the C3a-functionalized hexahydropyrroloA C H T U N G T R E N N U N G [2,3-b]indoles. A slightly lower transition-state energy in the generation of the corresponding spirane favors the exo product formation.…”

“…To set the right configuration at C2/C2', we took full advantage of the thermodynamic preference of exo-2-acyl hexahydropyrroloA C H T U N G T R E N N U N G [2,3-b]indoles to place the acyl group at the endo position under basic equilibrating conditions. [11] This striking bias for the endo isomer, which has been attributed to torsional interactions around the bicycloA C H T U N G T R E N N U N G [3.3.0]octane nucleus, [18] provided a significant flexibility to our methodology. Thus, treatment of the exo dimer 16 a with 4 equivalents of lithium bis(trimethylsilyl)amide (LiHMDS) at À15 8C in THF, followed by quenching of the corresponding lithium enolates with MeOH at À78 8C, afforded the diastereomeric endo dimer 25 in almost quantitative yield (Scheme 7).…”

Structure, Bioactivity and Synthesis of Natural Products with Hexahydropyrrolo[2,3‐b]indole

“…The literature contains a few reviews, although these appear to cover only specific aspects of these compounds. These include works by Schmidt and Movassaghi, [97] on biosynthetic hypotheses; Steven and Overman, [98] on syntheses of poly-HPI compounds; and Crich and Banerjee, [99] on the stereochemistry of HPI containing-compounds, as well as classical publications on the Calabar bean alkaloids, [100,101] phenserine, [102] chimonanthine and related natural products, [103,104] chaetocin and related natural products, [105] and the chemistry of cyclic tautomers of tryptamines and Trp. [106,107] This article provides an exhaustive overview of the structure, synthesis and bioactivity of HPI and HPIC containing natural products from all of the aforementioned structural classes, emphasizing the synthetic routes to polycyclic compounds of this type published until December 2009.…”

Total Synthesis of Indotertine A and Drimentines A, F, and G

“…[1] From a structural perspective, they can be divided into several classes that vary in the substituent on C3a of the pyrroloindoline core, including heteroatoms, arenes, aliphatic groups, and another pyrroloindoline motif. Accordingly, a series of strategies have been developed for the synthesis of the above pyrroloindoline classes.…”