Chemistry of the Hexahydropyrrolo2,3-bindoles:  Configuration, Conformation, Reactivity, and Applications in Synthesis

The stereoselective formation of 2-endo-substituted hexahydropyrrolo2,3-bindoles from 2-substituted tryptamine derivatives, especially tryptophan, is discussed. Parallels are drawn with the formation of related heterocyclic systems, such as the hexahydrofurano2,3-bbenzofurans, 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 diazabicyclo3.3.0octane 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 hexahydro2,3-bpyrroloindoles in the stereocontrolled synthesis of amino acids and alkaloids is presented.