Formal Synthesis of Gephyrotoxin

The synthesis of the Schmidt reaction precursor 42 is presented in Scheme 9. The vinyl bromide 29 was made as earlier described (see Scheme 7). Formation of the Grignard reagent derived from 29 followed by a copper-catalyzed opening of the epoxide 39[Ref.33] according to a procedure similar to that reported by Kocienski[Ref.34] gave the alcohol 40 in excellent yield. Mesylation of the alcohol and subsequent displacement with tetrabutylammonium azide and desilylation furnished the azide 41 in high yield. Mesylation of the primary alcohol 41 followed by bromide displacement afforded the desired Schmidt precursor 42.

Scheme 9. Preparation of the Key Azido-Alkene 42.

Treatment of 42 with triflic acid in benzene followed by sodium borohydride reduction of the resultant iminium ion generated a mixture of Schmidt products which were subjected, without purification, to bromide displacement using acetate ion. Again, without purification, the mixture of acetates was reduced with lithium aluminum hydride to produce a mixture of the desired alcohol 2, its stereoisomer 44, and the regioisomer 45 in good overall yield from 42. As in earlier attempts, the stereoselectivity of the reduction of the desired iminium ion was poor. We were able to overcome the nonselective reduction by switching to bulkier reducing agents. L-Selectride proved to be the most successful hydride reagent, ultimately producing the desired compound 2 as a single diastereomer (i.e., none of 44 was detected) accompanied by a small amount of the regioisomer 45. The overall yield of 2 from 42 using this procedure was 45%. Since the aromatic ring of 2 has been reduced by Ito, et. al[Ref.12] to afford an advanced intermediate in Kishi's synthesis of gephyrotoxin,[Ref.7] our synthesis of 2 constitutes a formal total synthesis of gephyrotoxin. The synthesis of 2 required 9 steps (5 purifications) from commercially available 4-methoxy-1-indanone 19, and proceeded in 22% overall yield.

Scheme 10. Completion of the Formal Total Synthesis of Gephyrotoxin


The intramolecular Schmidt reaction of azides with carbocations has proven to be an effective way to assemble the tricyclic core of the alkaloid gephyrotoxin, resulting in a formal total synthesis of this compound. The regioselectivity of aryl vs. alkyl migration to the electron deficient nitrogen of the aminodiazonium ion intermediate proved to be subject to small changes in the structure of the aryl group as well as remote functionality near the azide.


We thank the National Institutes of Health (GM-35572) for funding this research.

Links to the Rest of the Paper:

1. Introduction
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 (THIS PAGE) wherein we finally get it right.
5. References