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Aliphatic Azides in the Schmidt Reaction: A Formal Synthesis of Gephyrotoxin

William H. Pearson*and Wen-kui Fang

Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA
Tel. +(734)763-5837 Fax +(734)763-2307


Gephyrotoxin (1), originally isolated from Dendrobates histrionicus,[Ref.1] is a member of a class of alkaloids isolated from the skins of tropical frogs of the genus Dendrobates.[Ref.2] Its absolute configuration was determined to be as shown by X-ray analysis.[Ref.3] Gephyrotoxin is relatively nontoxic. Mild muscarinic activity was originally reported for this alkaloid,[Ref.4] however recent studies[Ref.5] have revealed a more complex and interesting array of neurological activities associated with gephyrotoxin. The low abundance in amphibians and the unusual chemical and biological characteristics of gephyrotoxin has led to synthetic interest in several laboratories.[Refs 6-12]

We recently disclosed the intra- and intermolecular Schmidt reactions of aliphatic azides with carbocations, a method that shows promise for the construction of cyclic and acyclic tertiary amines.[Refs 13-17] Here we report a formal total synthesis of gephyrotoxin using this synthetic protocol. A retrosynthetic analysis is shown in Scheme 1. Ito has prepared 2 and converted it to gephyrotoxin.[Ref.12] We planned to intercept Ito's intermediate by the stereoselective reduction of the iminium ion 3. This iminium ion would result from a Schmidt reaction of the azido-alkene 5, proceeding through the aminodiazonium ion 4 by aryl migration. The azido-alkene 5 should be available from the indene 6 by deprotonation and alkylation. The stereoselectivity of the iminium ion reduction, the regioselectivity of the Schmidt reaction, and the regioselectivity of the indene alkylation are all interesting issues to be examined. Before disclosing the formal synthesis of racemic gephyrotoxin,model studies will be described which deals with the viability of the basic Schmidt reaction for the assembly of the three rings of this alkaloid. Proceed to model studies.

Scheme 1. Retrosynthetic analysis of gephyrotoxin.


Links to the Rest of the Paper:

1. Introduction (THIS PAGE)
2. Model Studies: The Basic Schmidt Reaction, wherein we study the regioselectivity of the rearrangement and the stereoselectivity of the iminium ion reduction.

A. Regioselectivity of the Schmidt Reaction: Assembly of the Basic Core of Gephyrotoxin.
B. The Use of a Secondary Azide: Stereoselectivity of the Iminium Ion Reduction.

3. Initial Efforts to Synthesize Gephyrotoxin, wherein we struggle with the regioselectivity of the indene alkylation and the choice of a synthetic equivalent for the 2-hydroxyethyl side chain.

C. Alkylation of Methoxyindene and Schmidt Reactions of Regioisomeric Azidoindenes
D. Regiocontrolled Routes to the Cyclization Precusors: Avoid Indene Alkylations

4. Formal Synthesis of Gephyrotoxin, wherein we finally get it right.
5. References