Studies on the 4-Dimethylallyltryptophan Synthase Mechanism : Development of a Divinylcyclopropane Rearrangement based Strategy for the Formation of Cyclohepta[cd]oxindoles and its Application on the Synthesis of 5-(10⟶ 9)Abeo-Ergot Alkaloids

Abstract

1. Experimental evidence was found to support the enzymatic [3,3]-sigmatropic rearrangement catalysed by dimethylallyltryptophan (DMAT) synthase. A bio-inspired system showed the feasibility of Cope rearrangement to the C-4 position of the indole nucleus. This experiment supports the theory which says that 4-DMATS reverse prenylates C-3 and catalyses the Cope rearrangement into C-4. 2. A new methodology for the construction of cyclohepta[cd]oxindoles has been established. The presented methodology is intended to serve as a general approach to the functionalization of the 4-position of indole. It serves as an alternative to reactions where the toxic elements thallium and mercury are used, and offers broader scope compared to the Witkop cyclisation. The reaction is generally not affected by substituents on the aromatic core and tolerates many functional groups at the cyclopropane and the olefinic parts. 3. This work features the synthetic approach towards 5(10⟶9)abeo-ergoline derivatives, unnatural products derived from methyl lysergate. The key features of our synthesis is the divinylcyclopropane rearrangement to establish the tricyclic cyclohepta[cd]indole core. Gold (I) catalysis and Jeffrey cross coupling conditions furnished the pyrrolidine moiety and completed the carbon skeleton. Nevertheless, the adverse alignment of the orbitals on C- 9 and C-10, that could be proven by force field calculations, prevented the completion of our common intermediate. 4. The mechanism of the divinylcyclopropane rearrangement for the formation of cyclohepta- [cd]oxindoles has been investigated with respect to the dependence of the rate constants k and the cis-trans isomerization on the Thorpe-Ingold effect. The presence of a substituent on C-9 revealed a great increase of the rate constant compared to the unsubstituted compound. Furthermore, the cis-trans isomerization could be detected by NMR by using the C-9 nor-alkyl compound. Moreover, X-ray single crystal structure of the two corresponding trans-aldehydes showed the influence of the Thorpe-Ingold effect on the molecules.