Oxidative Cyclizations via the Pummerer Reaction

Many alkaloids appear to be biosynthesized by oxidative cyclizations on electron rich heterocyclic substrates.  Attempts to duplicate these processes in the laboratory (biomimetic synthesis) have led to mixed results, and some common problems that thwart this strategy have been identified: (1) product (over)oxidation, and (2) poor regiochemical control of cyclization in a multifunctional heterocyclic substrate.  One possible solution to these problems might utilize a transformation whose distinguishing characteristics include (1) separation of the oxidation and cyclization steps, so overoxidation can be avoided, and (2) electronic biases to steer the regiochemistry of nucleophile addition in a predictable manner.  An extended version of the Pummerer reaction on a heterocycle nucleus (shown below as an indole for convenience) fits this description.  Formal transfer of a unit of oxidation from the C(2) sulfur atom to C(3) of the indole core provides the means to favor nucleophile addition at that position.  3,3-Spirocyclic indolenines result, and these species can be readily converted to oxindoles or related compounds of significant value in natural products synthesis.

Several natural product targets that embody this type of framework/functionality have been identified.  These projects are all ongoing, and in each case the key Pummerer-based oxidative cyclization reaction has been demonstrated to occur with facility.  Note that oxidative cyclization of an imidazole substrate rather than an indole underlies the approach to dibromophakellin.

Current Target