A Concise Synthesis of Butylcycloheptylprodigiosin

Link: Org Lett ASAP

Jonathan T. Reeves*

Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877

A total synthesis in racemic form of butylcycloheptylprodigiosin in a very short sequence by a single author.

The key reaction was installation of the 2-formyl pyrrole ring in 4 based on previously reported method as shown below.

The synthesis started with enone 6. A sequence of 1,4-addition to 6 and trapping with oxazole 7 led to 5. Treatment of 5 based on previous method afforded 4 in good yield.

The rate of cyclization of enone type B in Figure 3 was tested. Dehydration of 5 led to 6:1 mixture of E-8 and Z-8 which could be separated by chromatography. E-8 was found to convert to 4 faster than Z-8 probably because of torsional strain of the enone in Z-8 which prevented optimal conjugation and thus rendering C-2 of oxazole ring less reactive towards hydrolysis in with base.

The total synthesis was completed according to the following sequence. Installation of triflate group, for Suzuki-Miyaura cross-coupling, was pretty cool. The conversion of 3 to 1 followed the Furstner protocol of the total synthesis of the same molecule accomplished previously.

The current total synthesis was accomplished in 5 steps from 6, which compared favorably with Furstner's 16 linear steps from 1,4-cyclononadien-3-one.